rs9282681

Positions:

• chr16-89739506-T-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_000135.4(FANCA):​c.3982A>G​(p.Thr1328Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0777 in 1,551,258 control chromosomes in the GnomAD database, including 5,562 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 Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T1328I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.060 (421 hom., cov: 33)
  • Exomes 𝑓: 0.080 (5141 hom.)
• Consequence: FANCA NM_000135.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts P:1 B:7 O:1
• Conservation: PhyloP100: -0.994

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 -18 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 10 uncertain in NM_000135.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.007843435).
• BP6: Variant 16-89739506-T-C is Benign according to our data. Variant chr16-89739506-T-C is described in ClinVar as [Benign]. Clinvar id is 134278.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-89739506-T-C is described in Lovd as [Pathogenic].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.209 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FANCA	NM_000135.4	c.3982A>G	p.Thr1328Ala	missense_variant	40/43	ENST00000389301.8
ZNF276	NM_001113525.2	c.*1260T>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.3982A>G	p.Thr1328Ala	missense_variant	40/43	1	NM_000135.4	P1
ZNF276	ENST00000443381.7	c.*1260T>C		3_prime_UTR_variant	11/11	1	NM_001113525.2	P2

Frequencies

GnomAD3 genomes AF: 0.0596 AC: 9071 AN: 152126 Hom.: 420 Cov.: 33

Gnomad AFR AF: 0.0140

Gnomad AMI AF: 0.0230

Gnomad AMR AF: 0.0376

Gnomad ASJ AF: 0.0580

Gnomad EAS AF: 0.218

Gnomad SAS AF: 0.0263

Gnomad FIN AF: 0.0613

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0833

Gnomad OTH AF: 0.0569

GnomAD3 exomes AF: 0.0661 AC: 10322 AN: 156058 Hom.: 617 AF XY: 0.0661 AC XY: 5444 AN XY: 82302

Gnomad AFR exome AF: 0.0139

Gnomad AMR exome AF: 0.0210

Gnomad ASJ exome AF: 0.0563

Gnomad EAS exome AF: 0.238

Gnomad SAS exome AF: 0.0215

Gnomad FIN exome AF: 0.0609

Gnomad NFE exome AF: 0.0803

Gnomad OTH exome AF: 0.0568

GnomAD4 exome AF: 0.0797 AC: 111444 AN: 1399014 Hom.: 5141 Cov.: 34 AF XY: 0.0783 AC XY: 54032 AN XY: 690082

Gnomad4 AFR exome AF: 0.0112

Gnomad4 AMR exome AF: 0.0226

Gnomad4 ASJ exome AF: 0.0563

Gnomad4 EAS exome AF: 0.153

Gnomad4 SAS exome AF: 0.0222

Gnomad4 FIN exome AF: 0.0579

Gnomad4 NFE exome AF: 0.0870

Gnomad4 OTH exome AF: 0.0831

GnomAD4 genome AF: 0.0596 AC: 9078 AN: 152244 Hom.: 421 Cov.: 33 AF XY: 0.0575 AC XY: 4280 AN XY: 74430

Gnomad4 AFR AF: 0.0139

Gnomad4 AMR AF: 0.0375

Gnomad4 ASJ AF: 0.0580

Gnomad4 EAS AF: 0.219

Gnomad4 SAS AF: 0.0272

Gnomad4 FIN AF: 0.0613

Gnomad4 NFE AF: 0.0833

Gnomad4 OTH AF: 0.0572

Alfa AF: 0.0796 Hom.: 871

Bravo AF: 0.0572

TwinsUK AF: 0.0984 AC: 365

ALSPAC AF: 0.0823 AC: 317

ESP6500AA AF: 0.0136 AC: 57

ESP6500EA AF: 0.0706 AC: 579

ExAC AF: 0.0307 AC: 2659

Asia WGS AF: 0.113 AC: 392 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1 Benign:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3 Other:1

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 06, 2016	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 18, 2021	Variant summary: FANCA c.3982A>G (p.Thr1328Ala) results in a non-conservative amino acid change in the encoded protein sequence. Two of three in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.066 in 156058 control chromosomes in the gnomAD database, including 617 homozygotes. The observed variant frequency is approximately 30.55 fold of the estimated maximal expected allele frequency for a pathogenic variant in FANCA causing Fanconi Anemia phenotype (0.0022), strongly suggesting that the variant is benign. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Five classified the variant as benign while one classified as pathogenic. Based on the evidence outlined above, the variant was classified as benign. -

Fanconi anemia complementation group A Pathogenic:1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Aug 23, 2019	- -
Pathogenic, flagged submission	curation	Leiden Open Variation Database	Feb 28, 2020	Curator: Arleen D. Auerbach. Submitter to LOVD: Arleen D. Auerbach. -

Fanconi anemia Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 12, 2019

This variant is associated with the following publications: (PMID: 31586946, 9371798, 27121516) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	0.11
DANN	Benign	0.44
DEOGEN2	Benign	0.14	T;.;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.35	N
LIST_S2	Benign	0.42	T;T;T
MetaRNN	Benign	0.0078	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.83	L;L;.
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.85	N;N;N
REVEL	Benign	0.20
Sift	Benign	0.44	T;T;T
Sift4G	Benign	0.26	T;T;T
Polyphen		0.0050	B;.;.
Vest4		0.017
ClinPred		0.00030	T
GERP RS		-1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.031
gMVP		0.10

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs9282681; hg19: chr16-89805914; COSMIC: COSV57066209; COSMIC: COSV57066209;