rs878853666

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000135.4(FANCA):c.752C>T(p.Ser251Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,842 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

FANCA
NM_000135.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:3

Conservation

PhyloP100: -0.0750

Publications

1 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: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FANCA	NM_000135.4 link	c.752C>T	p.Ser251Leu	missense_variant	Exon 8 of 43	ENST00000389301.8	NP_000126.2	O15360-1
FANCA	NM_001286167.3 link	c.752C>T	p.Ser251Leu	missense_variant	Exon 8 of 43		NP_001273096.1	O15360-3
FANCA	NM_001018112.3 link	c.752C>T	p.Ser251Leu	missense_variant	Exon 8 of 11		NP_001018122.1	O15360-2
FANCA	NM_001351830.2 link	c.656C>T	p.Ser219Leu	missense_variant	Exon 7 of 10		NP_001338759.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FANCA	ENST00000389301.8 link	c.752C>T	p.Ser251Leu	missense_variant	Exon 8 of 43	1	NM_000135.4	ENSP00000373952.3		O15360-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461842

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727226

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111980

Other (OTH)

AF:

0.0000166

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Fanconi anemia complementation group A

Uncertain:2

Sep 16, 2020

Natera, Inc.

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Apr 17, 2018

Counsyl

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Fanconi anemia

Uncertain:1

Oct 05, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces serine with leucine at codon 251 of the FANCA protein (p.Ser251Leu). The serine residue is moderately conserved and there is a large physicochemical difference between serine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with FANCA-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.54

CADD

Benign

1.1

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.20

T;.;.;T;T;.

Eigen

Benign

-0.64

Eigen_PC

Benign

-0.67

FATHMM_MKL

Benign

0.040

LIST_S2

Benign

0.76

T;T;T;T;T;T

M_CAP

Benign

0.034

MetaRNN

Benign

0.086

T;T;T;T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.5

L;L;L;.;.;.

PhyloP100

-0.075

PrimateAI

Benign

0.27

PROVEAN

Benign

-1.6

N;N;D;D;D;D

REVEL

Benign

0.040

Sift

Benign

0.13

T;T;T;D;T;T

Sift4G

Uncertain

0.033

D;D;D;D;D;D

Polyphen

0.013

B;.;B;.;B;B

Vest4

0.086

MutPred

0.28

Loss of disorder (P = 0.0267);Loss of disorder (P = 0.0267);Loss of disorder (P = 0.0267);Loss of disorder (P = 0.0267);Loss of disorder (P = 0.0267);.;

MVP

0.61

ClinPred

0.063

GERP RS

2.9

Varity_R

0.033

gMVP

0.15

Mutation Taster

=91/9

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.33

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.33

Position offset: -40

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over