chr16-89745047-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000135.4(FANCA):c.3538G>A(p.Val1180Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000576 in 1,607,800 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1180L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00029 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00061 ( 10 hom. )

Consequence

FANCA
NM_000135.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6O:1

Conservation

PhyloP100: 0.846

Publications

3 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=0.008875608).

BP6

Variant 16-89745047-C-T is Benign according to our data. Variant chr16-89745047-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 134270.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000289 (44/152318) while in subpopulation SAS AF = 0.0087 (42/4828). AF 95% confidence interval is 0.00661. There are 1 homozygotes in GnomAd4. There are 32 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FANCA	NM_000135.4 link	c.3538G>A	p.Val1180Met	missense_variant	Exon 36 of 43	ENST00000389301.8	NP_000126.2	O15360-1
FANCA	NM_001286167.3 link	c.3538G>A	p.Val1180Met	missense_variant	Exon 36 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.3538G>A	p.Val1180Met	missense_variant	Exon 36 of 43	1	NM_000135.4	ENSP00000373952.3		O15360-1

Frequencies

GnomAD3 genomes

AF:

0.000283

AC:

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00849

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00128

AC:

310

AN:

241552

AF XY:

0.00164

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000913

Gnomad OTH exome

AF:

0.000336

GnomAD4 exome

AF:

0.000606

AC:

882

AN:

1455482

Hom.:

Cov.:

AF XY:

0.000871

AC XY:

631

AN XY:

724172

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33424

American (AMR)

AF:

0.00

AC:

AN:

44546

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26082

East Asian (EAS)

AF:

0.00

AC:

AN:

39634

South Asian (SAS)

AF:

0.00983

AC:

844

AN:

85890

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48622

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00000450

AC:

AN:

1111302

Other (OTH)

AF:

0.000531

AC:

AN:

60220

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

148

222

296

370

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.000289

AC:

AN:

152318

Hom.:

Cov.:

AF XY:

0.000430

AC XY:

AN XY:

74496

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41578

American (AMR)

AF:

0.0000654

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00870

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68036

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.524

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.000152

Hom.:

Bravo

AF:

0.0000491

ExAC

AF:

0.00143

AC:

173

Asia WGS

AF:

0.00577

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Fanconi anemia complementation group A

Benign:3

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Aug 09, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely 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

- -

Jan 07, 2016

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Fanconi anemia

Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Jan 30, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

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

0.12

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.24

CADD

Benign

8.7

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.25

T;.;.

Eigen

Benign

-0.47

Eigen_PC

Benign

-0.47

FATHMM_MKL

Benign

0.60

LIST_S2

Benign

0.61

T;T;T

MetaRNN

Benign

0.0089

T;T;T

MetaSVM

Uncertain

0.064

MutationAssessor

Benign

1.2

L;L;.

PhyloP100

0.85

PrimateAI

Benign

0.30

PROVEAN

Benign

-1.2

N;N;N

REVEL

Benign

0.23

Sift

Uncertain

0.014

D;D;D

Sift4G

Benign

0.081

T;T;T

Polyphen

0.0090

B;.;.

Vest4

0.18

MutPred

0.28

Loss of catalytic residue at V1180 (P = 0.0624);Loss of catalytic residue at V1180 (P = 0.0624);.;

MVP

0.89

ClinPred

0.029

GERP RS

4.4

PromoterAI

-0.015

Neutral

(source)

RBP_binding_hub_radar

1.0

RBP_regulation_power_radar

2.2

Varity_R

0.044

gMVP

0.32

Mutation Taster

=98/2

polymorphism

(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