rs17232910

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000135.4(FANCA):c.1927C>G(p.Pro643Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.078 in 1,550,812 control chromosomes in the GnomAD database, including 5,683 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P643R) has been classified as Benign.

Frequency

Genomes: 𝑓 0.060 ( 437 hom., cov: 32)

Exomes 𝑓: 0.080 ( 5246 hom. )

Consequence

FANCA
NM_000135.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8O:1

Conservation

PhyloP100: 0.0740

Publications

33 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0039646924).

BP6

Variant 16-89773358-G-C is Benign according to our data. Variant chr16-89773358-G-C is described in ClinVar as Benign. ClinVar VariationId is 134247.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.223 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FANCA	NM_000135.4 link	c.1927C>G	p.Pro643Ala	missense_variant	Exon 22 of 43	ENST00000389301.8	NP_000126.2	O15360-1
FANCA	NM_001286167.3 link	c.1927C>G	p.Pro643Ala	missense_variant	Exon 22 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.1927C>G	p.Pro643Ala	missense_variant	Exon 22 of 43	1	NM_000135.4	ENSP00000373952.3		O15360-1

Frequencies

GnomAD3 genomes

AF:

0.0602

AC:

9162

AN:

152146

Hom.:

436

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0140

Gnomad AMI

AF:

0.0230

Gnomad AMR

AF:

0.0379

Gnomad ASJ

AF:

0.0591

Gnomad EAS

AF:

0.233

Gnomad SAS

AF:

0.0269

Gnomad FIN

AF:

0.0613

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0834

Gnomad OTH

AF:

0.0550

GnomAD2 exomes

AF:

0.0677

AC:

10573

AN:

156116

AF XY:

0.0674

show subpopulations

Gnomad AFR exome

AF:

0.0142

Gnomad AMR exome

AF:

0.0211

Gnomad ASJ exome

AF:

0.0571

Gnomad EAS exome

AF:

0.257

Gnomad FIN exome

AF:

0.0594

Gnomad NFE exome

AF:

0.0809

Gnomad OTH exome

AF:

0.0585

GnomAD4 exome

AF:

0.0800

AC:

111828

AN:

1398546

Hom.:

5246

Cov.:

AF XY:

0.0786

AC XY:

54209

AN XY:

689814

show subpopulations

African (AFR)

AF:

0.0111

AC:

352

AN:

31596

American (AMR)

AF:

0.0227

AC:

811

AN:

35702

Ashkenazi Jewish (ASJ)

AF:

0.0578

AC:

1455

AN:

25176

East Asian (EAS)

AF:

0.163

AC:

5832

AN:

35714

South Asian (SAS)

AF:

0.0225

AC:

1786

AN:

79236

European-Finnish (FIN)

AF:

0.0569

AC:

2795

AN:

49124

Middle Eastern (MID)

AF:

0.0132

AC:

AN:

5698

European-Non Finnish (NFE)

AF:

0.0870

AC:

93854

AN:

1078310

Other (OTH)

AF:

0.0839

AC:

4868

AN:

57990

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.449

Heterozygous variant carriers

4994

9988

14983

19977

24971

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3536

7072

10608

14144

17680

<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:

0.0602

AC:

9169

AN:

152266

Hom.:

437

Cov.:

AF XY:

0.0582

AC XY:

4337

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.0140

AC:

580

AN:

41542

American (AMR)

AF:

0.0378

AC:

579

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0591

AC:

205

AN:

3468

East Asian (EAS)

AF:

0.234

AC:

1210

AN:

5180

South Asian (SAS)

AF:

0.0278

AC:

134

AN:

4828

European-Finnish (FIN)

AF:

0.0613

AC:

650

AN:

10612

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0834

AC:

5672

AN:

68016

Other (OTH)

AF:

0.0553

AC:

117

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

456

912

1369

1825

2281

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

220

330

440

550

<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:

0.0805

Hom.:

433

Bravo

AF:

0.0580

TwinsUK

AF:

0.0987

AC:

366

ALSPAC

AF:

0.0830

AC:

320

ESP6500AA

AF:

0.0125

AC:

ESP6500EA

AF:

0.0659

AC:

519

ExAC

AF:

0.0245

AC:

1457

Asia WGS

AF:

0.117

AC:

407

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:8Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Fanconi anemia complementation group A

Benign:4

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 15, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 06, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1Other:1

Sep 19, 2013

ITMI

Significance:not provided

Review Status:no classification provided

Collection Method:reference population

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Fanconi anemia

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.42

CADD

Benign

0.76

(source)

DANN

Benign

0.37

DEOGEN2

Benign

0.19

T;.

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.033

LIST_S2

Benign

0.41

T;T

MetaRNN

Benign

0.0040

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.97

L;L

PhyloP100

0.074

PrimateAI

Benign

0.28

PROVEAN

Uncertain

-2.5

N;N

REVEL

Benign

0.23

Sift

Benign

0.45

T;T

Sift4G

Benign

0.39

T;T

Polyphen

0.0010

B;.

Vest4

0.032

ClinPred

0.0011

GERP RS

-2.4

RBP_binding_hub_radar

1.0

RBP_regulation_power_radar

2.1

Varity_R

0.019

gMVP

0.24

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

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