16-89738893-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_000135.4(FANCA):c.4249C>G(p.His1417Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00412 in 1,614,250 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. H1417H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0035 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0042 (15 hom.)
• Consequence: FANCA NM_000135.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2 B:12 O:1
• Conservation: PhyloP100: -0.490

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0046495795).
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00349 (532/152380) while in subpopulation AMR AF= 0.00471 (72/15302). AF 95% confidence interval is 0.00386. There are 1 homozygotes in gnomad4. There are 289 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FANCA	NM_000135.4	c.4249C>G	p.His1417Asp	missense_variant	42/43	ENST00000389301.8
ZNF276	NM_001113525.2	c.*647G>C		3_prime_UTR_variant	11/11	ENST00000443381.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FANCA	ENST00000389301.8	c.4249C>G	p.His1417Asp	missense_variant	42/43	1	NM_000135.4	P1
ZNF276	ENST00000443381.7	c.*647G>C		3_prime_UTR_variant	11/11	1	NM_001113525.2	P2

Frequencies

GnomAD3 genomes AF: 0.00349 AC: 532 AN: 152262 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00123

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00471

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00969

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00426

Gnomad OTH AF: 0.00430

GnomAD3 exomes AF: 0.00346 AC: 870 AN: 251482 Hom.: 4 AF XY: 0.00349 AC XY: 475 AN XY: 135920

Gnomad AFR exome AF: 0.000984

Gnomad AMR exome AF: 0.00289

Gnomad ASJ exome AF: 0.000198

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000653

Gnomad FIN exome AF: 0.00993

Gnomad NFE exome AF: 0.00427

Gnomad OTH exome AF: 0.00505

GnomAD4 exome AF: 0.00419 AC: 6125 AN: 1461870 Hom.: 15 Cov.: 35 AF XY: 0.00411 AC XY: 2987 AN XY: 727234

Gnomad4 AFR exome AF: 0.000627

Gnomad4 AMR exome AF: 0.00295

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000777

Gnomad4 FIN exome AF: 0.0117

Gnomad4 NFE exome AF: 0.00455

Gnomad4 OTH exome AF: 0.00339

GnomAD4 genome AF: 0.00349 AC: 532 AN: 152380 Hom.: 1 Cov.: 33 AF XY: 0.00388 AC XY: 289 AN XY: 74512

Gnomad4 AFR AF: 0.00123

Gnomad4 AMR AF: 0.00471

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00969

Gnomad4 NFE AF: 0.00426

Gnomad4 OTH AF: 0.00425

Alfa AF: 0.00375 Hom.: 3

Bravo AF: 0.00295

TwinsUK AF: 0.00539 AC: 20

ALSPAC AF: 0.00441 AC: 17

ESP6500AA AF: 0.000455 AC: 2

ESP6500EA AF: 0.00349 AC: 30

ExAC AF: 0.00339 AC: 412

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00398

EpiControl AF: 0.00403

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2 Benign:12 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:4 Other:1

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 03, 2022	Variant summary: FANCA c.4249C>G (p.His1417Asp) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0035 in 282888 control chromosomes, including 5 homozygotes (gnomAD). The variant occurs predominantly at a frequency of 0.0043 within the Non-Finnish European subpopulation in the gnomAD database, including 3 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in FANCA causing Fanconi Anemia (0.0022), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.4249C>G has been reported in the literature in at least one homozygous individual affected with Fanconi Anemia (Levran_1997). This report does not provide unequivocal conclusions about association of the variant with Fanconi Anemia. At least one publication reports experimental evidence evaluating the variant's effects on FANCA phosphorylation, interaction with FANCC, FANCF and FANCG and nuclear localization and FANCD2 monoubiquitination. These experiments showed the variant behaved similarly to wild-type (Adachi_2002). Nine ClinVar submitters have assessed the variant since 2014: one classified the variant as pathogenic, two as uncertain significance, two as likely benign, and four as benign. Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 26, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Jul 01, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 21, 2021	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 30, 2020	This variant is associated with the following publications: (PMID: 12444097, 27153395, 9371798, 25525159, 22995991, 24728327) -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	FANCA: BP4, BS2; ZNF276: BS2 -

Fanconi anemia complementation group A Pathogenic:1 Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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 did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Pathogenic, no assertion criteria provided	curation	Leiden Open Variation Database	Feb 28, 2020	Curator: Arleen D. Auerbach. Submitter to LOVD: Arleen D. Auerbach. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

Fanconi anemia Benign:2

Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Jun 25, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -

FANCA-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 31, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.33
Cadd	Benign	0.67
Dann	Benign	0.80
DEOGEN2	Benign	0.13	T;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.40	T;T
MetaRNN	Benign	0.0046	T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.20	N;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.42	N;N
REVEL	Benign	0.22
Sift	Benign	0.39	T;T
Sift4G	Benign	0.29	T;T
Polyphen		0.0	B;.
Vest4		0.25
MVP		0.71
ClinPred		0.00083	T
GERP RS		-6.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.024
gMVP		0.21

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs17227403; hg19: chr16-89805301; COSMIC: COSV104613995; COSMIC: COSV104613995;