chr16-89816551-C-T

Position:

chr16-89816551-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000135.4(FANCA):c.65G>A(p.Trp22*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000338 in 1,509,338 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 0.000039 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000033 ( 0 hom. )

Consequence

FANCA
NM_000135.4 stop_gained

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14

Conservation

PhyloP100: 0.325

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:

FANCA (HGNC:):

FANCA links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 174 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 16-89816551-C-T is Pathogenic according to our data. Variant chr16-89816551-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 550541.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-89816551-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FANCA	NM_000135.4 linkuse as main transcript	c.65G>A	p.Trp22*	stop_gained	1/43	ENST00000389301.8	NP_000126.2	O15360-1
FANCA	NM_001286167.3 linkuse as main transcript	c.65G>A	p.Trp22*	stop_gained	1/43		NP_001273096.1	O15360-3
FANCA	NM_001018112.3 linkuse as main transcript	c.65G>A	p.Trp22*	stop_gained	1/11		NP_001018122.1	O15360-2
FANCA	NM_001351830.2 linkuse as main transcript	c.65G>A	p.Trp22*	stop_gained	1/10		NP_001338759.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FANCA	ENST00000389301.8 linkuse as main transcript	c.65G>A	p.Trp22*	stop_gained	1/43	1	NM_000135.4	ENSP00000373952.3		O15360-1

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152104

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000122

AC:

AN:

106420

Hom.:

AF XY:

0.000117

AC XY:

AN XY:

59642

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00167

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000247

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000332

AC:

AN:

1357234

Hom.:

Cov.:

AF XY:

0.0000299

AC XY:

AN XY:

669956

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00128

Gnomad4 EAS exome

AF:

0.0000311

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000655

Gnomad4 OTH exome

AF:

0.000106

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152104

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74304

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00173

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000282

Hom.:

Bravo

AF:

0.0000453

ExAC

AF:

0.0000224

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Fanconi anemia complementation group A

Pathogenic:7

Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	The FANCA c.65G>A (p.Trp22Ter) variant is a stop-gained variant that is predicted to result in premature termination of the protein. The p.Trp22Ter variant has been reported in at least three studies in which it is found in a total of five individuals with Fanconi anemia, including in two in a compound heterozygous state with a frameshift variant and in three in a heterozygous state without a second identified variant (Levran et al. 1997; Castella et al. 2011; De Rocco et al. 2014). The p.Trp22Ter variant was absent from four controls and is reported at a frequency of 0.00071 in the European (non-Finnish) population of the Exome Aggregation Consortium but this is based on two alleles only in a region of poor sequence coverage. Based on the evidence and the potential impact of stop-gained variants, the p.Trp22Ter variant is classified as likely pathogenic for Fanconi anemia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 25, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 24, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota	Jun 30, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jan 03, 2020	NM_000135.2(FANCA):c.65G>A(W22) is classified as pathogenic in the context of Fanconi anemia. Sources cited for classification include the following: PMID 15643609, 19367192 and 29098742. Classification of NM_000135.2(FANCA):c.65G>A(W22) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, no assertion criteria provided	curation	Leiden Open Variation Database	Feb 28, 2020	Curator: Arleen D. Auerbach. Submitter to LOVD: Arleen D. Auerbach. -

not provided

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Aug 21, 2020	PVS1, PS1, PS4, PM2 -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jan 25, 2022	This nonsense variant causes the premature termination of FANCA protein synthesis. The frequency of this variant in the general population, 0.0017 (6/3470 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with Fanconi anemia, complementation group A, and is considered an Ashkenazi Jewish founder mutation (PMIDs: 29098742 (2018), 24584348 (2014), 21273304 (2011), 19367192 (2009), 15643609 (2005), 9371798 (1997)). Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 14, 2020	DNA sequence analysis of the FANCA gene demonstrated a base pair change, c.65G>A, which results in the creation of a premature stop codon at amino acid residue 22, p.Trp22. This sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated FANCA protein with potentially abnormal function. The p.Trp22 change has been described in several individuals with a clinical diagnosis of Fanconi anemia (PMIDs: 9371798, 29098742); both in the homozygous (PMID: 31558676) and compound heterozgyous state (PMIDs: 31558676, 9711872, 19367192). This sequence change is present in the gnomAD database with a frequency of 0.17% in the Ashkenzi Jewish sub-population (dbSNP rs761341952). These collective evidences indicate that this sequence change is pathogenic, however functional studies have not been performed to prove this conclusively. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 15, 2024	Identified with a second variant, phase unknown, in multiple individuals with Fanconia anemia in published literature (PMID: 19367192, 29098742); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 15643609, 19367192, 21273304, 28717661, 29098742, 31558676) -

Fanconi anemia

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	This sequence change creates a premature translational stop signal (p.Trp22*) in the FANCA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in FANCA are known to be pathogenic (PMID: 19367192). This variant is present in population databases (rs761341952, gnomAD 0.2%). This premature translational stop signal has been observed in individual(s) with Fanconi anemia (PMID: 9711872, 15643609, 19367192, 28717661, 29098742). ClinVar contains an entry for this variant (Variation ID: 550541). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Apr 27, 2021	- -

FANCA-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 17, 2024

The FANCA c.65G>A variant is predicted to result in premature protein termination (p.Trp22*). This variant has been reported to be causative for Fanconi anemia (Levran et al. 1997. PubMed ID: 9371798; Castella et al. 2011. PubMed ID: 21273304; Steinberg-Shemer et al. 2019. PubMed ID: 31558676). This variant is reported in 0.17% of alleles in individuals of Ashkenazi Jewish descent in gnomAD and is interpreted as likely pathogenic/pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/550541/). Nonsense variants in FANCA are expected to be pathogenic. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.25

CADD

Pathogenic

DANN

Benign

0.97

Eigen

Benign

0.025

Eigen_PC

Benign

-0.33

FATHMM_MKL

Benign

0.55

Vest4

0.72

GERP RS

1.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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