16-89816614-A-G

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1PS1_ModeratePM2PP5_Very_Strong

The NM_000135.4(FANCA):c.2T>C(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000282 in 1,524,328 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000026 ( 0 hom. )

Consequence

FANCA
NM_000135.4 start_lost

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12

Conservation

PhyloP100: 1.06

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 20 ACMG points.

PVS1

Start lost variant, next in-frame start position is after 21 pathogenic variants. Next in-frame start position is after 345 CDS bases. Genomic position: 89811010. Lost 0.079 part of the original CDS.

PS1

Another start lost variant in NM_000135.4 (FANCA) was described as [Pathogenic] in Lovd

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 16-89816614-A-G is Pathogenic according to our data. Variant chr16-89816614-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 554309.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-89816614-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FANCA	NM_000135.4 link	c.2T>C	p.Met1?	start_lost	Exon 1 of 43	ENST00000389301.8	NP_000126.2	O15360-1
FANCA	NM_001286167.3 link	c.2T>C	p.Met1?	start_lost	Exon 1 of 43		NP_001273096.1	O15360-3
FANCA	NM_001018112.3 link	c.2T>C	p.Met1?	start_lost	Exon 1 of 11		NP_001018122.1	O15360-2
FANCA	NM_001351830.2 link	c.2T>C	p.Met1?	start_lost	Exon 1 of 10		NP_001338759.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FANCA	ENST00000389301.8 link	c.2T>C	p.Met1?	start_lost	Exon 1 of 43	1	NM_000135.4	ENSP00000373952.3		O15360-1

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152032

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.0000944

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000414

AC:

AN:

120628

Hom.:

AF XY:

0.0000745

AC XY:

AN XY:

67104

show subpopulations

Gnomad AFR exome

AF:

0.000313

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000142

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000211

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000262

AC:

AN:

1372296

Hom.:

Cov.:

AF XY:

0.0000354

AC XY:

AN XY:

677952

show subpopulations

Gnomad4 AFR exome

AF:

0.0000343

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000167

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000186

Gnomad4 OTH exome

AF:

0.0000349

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152032

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74278

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.0000944

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000435

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000320

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Fanconi anemia complementation group A

Pathogenic:8

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 25, 2017

Counsyl

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 27, 2022

Genetics and Genomic Medicine Centre, NeuroGen Healthcare, NeuroGen Healthcare

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The start loss variant c.2T>C (p.Met1?) in FANCA gene has been reported previously in individuals affected with Fanconia anemia (Levran et al., 2005; Gille et al., 2012). In addition, other variants that also affect the initiator methionine of the FANCA mRNA (c.1A>T, c.1A>G, and c.2T>A) have been reported in individuals affected with Fanconi anemia (Chandra et al., 2005). The c.2T>C (p.Met1?) variant is reported with the allele frequency (0.004%) in the gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic. The variant is predicted to be damaging by both SIFT and PolyPhen2. The residue is conserved across species. The nucleotide change in FANCA is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -

Jan 25, 2023

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

The heterozygous p.Met1Thr variant in FANCA was identified by our study, in the compound heterozygous state with a likely pathogenic variant (ClinVar Variation ID: 582405) in one individual with Fanconi anemia. Trio exome sequencing analysis revealed that this variant was in trans with another likely pathogenic variant (ClinVar Variation ID: 582405). The p.Met1Thr variant in FANCA has been previously reported in at least six unrelated individuals with Fanconi anemia complementation group A (PMID: 28060124, PMID: 30792206, PMID: 19367192, PMID: 30031030, PMID: 23898106, PMID: 10090479, PMID: 22778927) and segregated with disease in 3 affected members in one family (PMID: 28060124), but has been identified in 0.01% (3/21056) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs769479800). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. This variant has also been reported in ClinVar (Variation ID: 554309) and has been interpreted as pathogenic by Counsyl, Mayo Clinic Laboratories, GeneDx, Invitae, the Leiden Open Variant Database, Natera, Inc, and PerkinElmer Genomics. Of these six unrelated individuals who were previously reported (PMID: 28060124, PMID: 30792206, PMID: 19367192, PMID: 30031030, PMID: 23898106, PMID: 10090479, PMID: 22778927), one was a homozygote (PMID: 10090479), and four were compound heterozygotes who carried a pathogenic or likely pathogenic variants in trans (PMID: 28060124, ClinVar Variation ID: 545114; PMID: 30792206; PMID: 19367192; PMID: 23898106, ClinVar Variation ID: 41003) and one was a compound heterozygote who carried a variant of uncertain significance in trans (PMID: 30031030), and, in addition, the variant was found in trans with a pathogenic variant in the individual identified by our study (ClinVar Variation ID: 582405), which increases the likelihood that the p.Met1Thr variant is pathogenic. Five additional pathogenic or likely pathogenic variants, resulting in a different amino acid change at the same position, c.1A>G (p.Met1Val), c.1A>C (p.Met1Leu), c.1A>T (p.Met1Leu), c.2T>A (p.Met1Lys), c.2T>G (p.Met1Arg), and c.3G>T (p.Met1Ile), have been reported in association with disease in ClinVar, supporting that a change at this position may not be tolerated (Variation ID: 435134, 553521, 553965, 556239, 934462, 555802). In vitro functional studies provide some evidence that the p.Met1Thr variant may slightly impact protein function (PMID: 30031030). However, these types of assays may not accurately represent biological function. This variant is an initiation codon variant with closest in-frame potential start codon at in exon 4 at Met116 and there are 53 variants classified as pathogenic or likely pathogenic in ClinVar (access date 10/10/2022) upstream of closest in-frame potential start codon (Met116). Loss of function is an established disease mechanism of autosomal recessive Fanconi anemia complementation group A. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Fanconi anemia complementation group A. ACMG/AMP Criteria applied: PVS1_Moderate, PM3_VeryStrong, PS3_Supporting, PM5, PP1 (Richards 2015). -

Jun 25, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 28, 2020

Leiden Open Variation Database

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: curation

Curator: Arleen D. Auerbach. Submitters to LOVD: Arleen D. Auerbach, Johan de Winter. -

Mar 26, 2021

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Fanconi anemia

Pathogenic:2

Jan 19, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects the initiator methionine of the FANCA mRNA. The next in-frame methionine is located at codon 116. This variant is present in population databases (rs769479800, gnomAD 0.01%). Disruption of the initiator codon has been observed in individuals with Fanconi anemia (PMID: 10090479, 15643609, 16084127, 22778927, 23898106, 24584348). ClinVar contains an entry for this variant (Variation ID: 554309). For these reasons, this variant has been classified as Pathogenic. -

Oct 27, 2023

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: FANCA c.2T>C (p.Met1Thr) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. The next in-frame methionine is located at codon 116. Three of three in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.1e-05 in 120628 control chromosomes (gnomAD). c.2T>C has been reported in the literature in multiple individuals affected with Fanconi Anemia (examples: Levran_2005, Pinto_2009, Moghrabi_2009, Gille_2012, Li_2018, and Mori_2019). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, in this study this variant was not able to fully rescue MMC sensitivity (Li_2018). The following publications have been ascertained in the context of this evaluation (PMID: 22778927, 15643609, 30031030, 19367192, 30792206, 19278965). Other start loss variants have been classified pathogenic in ClinVar (CV ID 934462, 556239, 554309). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided

Pathogenic:2

Apr 14, 2020

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1_Moderate, PS3, PM2, PM3 -

Nov 28, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified in patients with Fanconi anemia referred for genetic testing at GeneDx and in published literature (Levran et al., 2005; Li et al., 2018; Mori et al., 2019); Published functional studies demonstrate a damaging effect (Li et al., 2018); Initiation codon variant in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 24584348, 10090479, 28060124, 30792206, 23898106, 22778927, 19367192, 16084127, 15643609, 31589614, 30031030) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Pathogenic

0.27

CADD

Benign

DANN

Benign

0.83

DEOGEN2

Benign

0.090

T;.;.;T;T;.

Eigen

Benign

-0.0089

Eigen_PC

Benign

-0.12

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.90

D;D;D;D;D;D

M_CAP

Pathogenic

0.99

MetaRNN

Pathogenic

0.99

D;D;D;D;D;D

MetaSVM

Uncertain

0.31

PROVEAN

Benign

-1.2

N;N;N;N;N;N

REVEL

Uncertain

0.45

Sift

Pathogenic

0.0

D;D;D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;D;D

Polyphen

0.90

P;.;.;.;D;D

Vest4

0.74

MutPred

1.0

Gain of phosphorylation at M1 (P = 0.0319);Gain of phosphorylation at M1 (P = 0.0319);Gain of phosphorylation at M1 (P = 0.0319);Gain of phosphorylation at M1 (P = 0.0319);Gain of phosphorylation at M1 (P = 0.0319);Gain of phosphorylation at M1 (P = 0.0319);

MVP

0.91

ClinPred

0.98

GERP RS

4.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.92

gMVP

0.24

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over