16-89775768-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 1P and 11B. PP3BP4_ModerateBP6BS1BS2

The NM_000135.4(FANCA):c.1874G>C(p.Cys625Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00258 in 1,612,748 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C625Y) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0022 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0026 ( 9 hom. )

Consequence

FANCA
NM_000135.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:9B:9

Conservation

PhyloP100: 4.72

Publications

20 publications found

Variant links:

Genes affected

FANCA (HGNC:3582): (FA complementation group A) The Fanconi anemia complementation group (FANC) currently includes FANCA, FANCB, FANCC, FANCD1 (also called BRCA2), FANCD2, FANCE, FANCF, FANCG, FANCI, FANCJ (also called BRIP1), FANCL, FANCM and FANCN (also called PALB2). The previously defined group FANCH is the same as FANCA. Fanconi anemia is a genetically heterogeneous recessive disorder characterized by cytogenetic instability, hypersensitivity to DNA crosslinking agents, increased chromosomal breakage, and defective DNA repair. The members of the Fanconi anemia complementation group do not share sequence similarity; they are related by their assembly into a common nuclear protein complex. This gene encodes the protein for complementation group A. Alternative splicing results in multiple transcript variants encoding different isoforms. Mutations in this gene are the most common cause of Fanconi anemia. [provided by RefSeq, Jul 2008]

FANCA Gene-Disease associations (from GenCC):

Fanconi anemia complementation group A
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, G2P
Fanconi anemia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

FANCA links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, BayesDel_addAF, BayesDel_noAF, M_CAP, PROVEAN, REVEL, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster, PrimateAI was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.19460729).

BP6

Variant 16-89775768-C-G is Benign according to our data. Variant chr16-89775768-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 265136.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00222 (338/152300) while in subpopulation NFE AF = 0.00392 (267/68028). AF 95% confidence interval is 0.00354. There are 0 homozygotes in GnomAd4. There are 145 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FANCA	NM_000135.4 link	c.1874G>C	p.Cys625Ser	missense_variant	Exon 21 of 43	ENST00000389301.8	NP_000126.2	O15360-1
FANCA	NM_001286167.3 link	c.1874G>C	p.Cys625Ser	missense_variant	Exon 21 of 43		NP_001273096.1	O15360-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FANCA	ENST00000389301.8 link	c.1874G>C	p.Cys625Ser	missense_variant	Exon 21 of 43	1	NM_000135.4	ENSP00000373952.3		O15360-1

Frequencies

GnomAD3 genomes

AF:

0.00222

AC:

338

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00157

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000377

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00392

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00236

AC:

587

AN:

249194

AF XY:

0.00235

show subpopulations

Gnomad AFR exome

AF:

0.000749

Gnomad AMR exome

AF:

0.00169

Gnomad ASJ exome

AF:

0.00120

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00116

Gnomad NFE exome

AF:

0.00385

Gnomad OTH exome

AF:

0.00180

GnomAD4 exome

AF:

0.00262

AC:

3820

AN:

1460448

Hom.:

Cov.:

AF XY:

0.00259

AC XY:

1884

AN XY:

726338

show subpopulations

African (AFR)

AF:

0.000389

AC:

AN:

33452

American (AMR)

AF:

0.00173

AC:

AN:

44574

Ashkenazi Jewish (ASJ)

AF:

0.000844

AC:

AN:

26072

East Asian (EAS)

AF:

0.00

AC:

AN:

39676

South Asian (SAS)

AF:

0.000955

AC:

AN:

85882

European-Finnish (FIN)

AF:

0.00124

AC:

AN:

53326

Middle Eastern (MID)

AF:

0.00104

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00308

AC:

3423

AN:

1111356

Other (OTH)

AF:

0.00217

AC:

131

AN:

60342

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

179

358

537

716

895

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

200

300

400

500

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00222

AC:

338

AN:

152300

Hom.:

Cov.:

AF XY:

0.00195

AC XY:

145

AN XY:

74470

show subpopulations

African (AFR)

AF:

0.000722

AC:

AN:

41550

American (AMR)

AF:

0.00157

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00173

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.000377

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00392

AC:

267

AN:

68028

Other (OTH)

AF:

0.00237

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00302

Hom.:

Bravo

AF:

0.00219

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.00285

AC:

ESP6500AA

AF:

0.000682

AC:

ESP6500EA

AF:

0.00314

AC:

ExAC

AF:

0.00240

AC:

291

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00311

EpiControl

AF:

0.00291

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:9Benign:9

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Fanconi anemia complementation group A

Pathogenic:1Uncertain:4Benign:2

May 18, 2021

Genome-Nilou Lab

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 07, 2022

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Feb 28, 2020

Leiden Open Variation Database

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:curation

Curator: Arleen D. Auerbach. Submitter to LOVD: Arleen D. Auerbach. -

Jul 11, 2023

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The FANCA c.1874G>C (p.Cys625Ser) missense change has a maximum subpopulation frequency of 0.39% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a deleterious effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. This variant has been reported in an individual with Fanconi anemia who also harbored a deletion of exons 18-20 in FANCA, however the phase of the two variants was not known (PMID: 21273304). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. -

May 08, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 23, 2025

Mendelics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following: it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease, and/or has normal protein function, and/or has lack of segregation with disease, and/or has been detected in co-occurrence with known pathogenic variant, and/or has lack of disease association in case-control studies, and/or is located in a region inconsistent with a known cause of pathogenicity. -

not specified

Uncertain:3Benign:3

Nov 02, 2016

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 15, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: FANCA c.1874G>C (p.Cys625Ser) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0026 in 1612748 control chromosomes, predominantly at a frequency of 0.0031 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately equal to the estimated maximal expected allele frequency for a pathogenic variant in FANCA causing Fanconi Anemia phenotype (0.0022) and the variant was found in 8 homozygotes, strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.1874G>C has been reported in the literature in at least two individuals affected with Fanconi Anemia, however in one case it was not considered to be pathogenic as it was reportedly located in cis downstream from a pathogenic variant and was also observed at a similar frequency in healthy controls (Castella_2011, De Rocco_2014). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 21273304, 24584348, 34864095). Multiple submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments. Ten submitters have classified the variant as uncertain significance, six submitters classified it as benign/likely benign, and one classified it as pathogenic. Based on the evidence outlined above, the variant was classified as benign. -

Jan 24, 2017

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The C625S variant in the FANCA gene has been previously reported in an individual with Fanconi anemia who also harbored a multi-exon FANCA deletion; however, the phase of these two variants was not confirmed, as parental testing was not performed (Castella et al., 2011). Although not present in the homozygous state, the NHLBI ESP Exome Sequencing Project reports C625S was observed in 27/8600 (0.31%) alleles from individuals of European background, indicating it may be a rare variant in this population. The C625S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret C625S as a variant of uncertain significance. -

May 13, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 01, 2016

Eurofins Ntd Llc (ga)

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 12, 2017

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Uncertain:2Benign:1

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 14, 2021

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

FANCA: BS2 -

Fanconi anemia

Benign:2

Jan 21, 2022

Sema4, Sema4

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:curation

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

FANCA-related disorder

Benign:1

Feb 02, 2022

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.58

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Pathogenic

0.47

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.71

D;.

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.77

T;T

M_CAP

Pathogenic

0.43

MetaRNN

Benign

0.19

T;T

MetaSVM

Pathogenic

1.0

MutationAssessor

Uncertain

2.8

M;M

PhyloP100

4.7

PrimateAI

Benign

0.47

PROVEAN

Pathogenic

-7.5

D;D

REVEL

Pathogenic

0.81

Sift

Uncertain

0.0060

D;D

Sift4G

Uncertain

0.022

D;D

Polyphen

0.99

D;.

Vest4

0.86

MutPred

0.58

Gain of disorder (P = 0.0348);Gain of disorder (P = 0.0348);

MVP

0.96

ClinPred

0.096

GERP RS

5.0

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.6

Varity_R

0.74

gMVP

0.70

Mutation Taster

=86/14

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over