rs587778321

chr16-89738696-G-Achr16-89738696-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_000135.4(FANCA):c.4273C>T(p.Arg1425Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000384 in 1,613,884 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1425G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000040 (1 hom.)
• Consequence: FANCA NM_000135.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:7 O:1
• Conservation: PhyloP100: 0.313

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]

ZNF276 (HGNC:23330): (zinc finger protein 276) Enables sequence-specific double-stranded DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Located in kinetochore. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 10 uncertain in NM_000135.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06801152).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FANCA	NM_000135.4	c.4273C>T	p.Arg1425Cys	missense_variant	43/43	ENST00000389301.8
ZNF276	NM_001113525.2	c.*450G>A		3_prime_UTR_variant	11/11	ENST00000443381.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FANCA	ENST00000389301.8	c.4273C>T	p.Arg1425Cys	missense_variant	43/43	1	NM_000135.4	P1
ZNF276	ENST00000443381.7	c.*450G>A		3_prime_UTR_variant	11/11	1	NM_001113525.2	P2

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152188 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000320 AC: 8 AN: 249676 Hom.: 0 AF XY: 0.0000370 AC XY: 5 AN XY: 135162

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000467

Gnomad NFE exome AF: 0.0000445

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000397 AC: 58 AN: 1461578 Hom.: 1 Cov.: 31 AF XY: 0.0000454 AC XY: 33 AN XY: 727082

Gnomad4 AFR exome AF: 0.000418

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000243

Gnomad4 OTH exome AF: 0.000166

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152306 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74480

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000473

Bravo AF: 0.0000227

ExAC AF: 0.0000247 AC: 3

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Fanconi anemia complementation group A Uncertain:5

Uncertain significance, criteria provided, single submitter	clinical testing	Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital	Nov 22, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Nov 08, 2021	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Feb 24, 2017	- -

Fanconi anemia Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Oct 25, 2022	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1425 of the FANCA protein (p.Arg1425Cys). This variant is present in population databases (rs587778321, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with FANCA-related conditions. ClinVar contains an entry for this variant (Variation ID: 134284). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt FANCA 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. -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Mar 09, 2022	- -

not specified Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.43
Cadd	Benign	2.3
Dann	Uncertain	0.99
DEOGEN2	Benign	0.097	T;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.63	T;T
M_CAP	Benign	0.085	D
MetaRNN	Benign	0.068	T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.86	L;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	0.080	N;N
REVEL	Benign	0.094
Sift	Benign	0.20	T;T
Sift4G	Benign	0.17	T;D
Polyphen		0.033	B;.
Vest4		0.093
MutPred		0.24		Loss of disorder (P = 0.0505);.;
MVP		0.66
ClinPred		0.049	T
GERP RS		-3.2
Varity_R		0.047
gMVP		0.23

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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

Other links and lift over

dbSNP: rs587778321; hg19: chr16-89805104; COSMIC: COSV57067061; COSMIC: COSV57067061;