rs35495399

chr3-10073349-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001018115.3(FANCD2):c.2702G>T(p.Gly901Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0299 in 1,611,202 control chromosomes in the GnomAD database, including 860 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (61 hom., cov: 32)
  • Exomes 𝑓: 0.031 (799 hom.)
• Consequence: FANCD2 NM_001018115.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8 O:1
• Conservation: PhyloP100: 1.64

Genes affected

FANCD2 (HGNC:3585): (FA complementation group D2) 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 D2. This protein is monoubiquinated in response to DNA damage, resulting in its localization to nuclear foci with other proteins (BRCA1 AND BRCA2) involved in homology-directed DNA repair. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2016]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0039370656).
• BP6: Variant 3-10073349-G-T is Benign according to our data. Variant chr3-10073349-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 134318.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-10073349-G-T is described in Lovd as [Benign]. Variant chr3-10073349-G-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0221 (3364/152232) while in subpopulation NFE AF= 0.0346 (2353/68032). AF 95% confidence interval is 0.0334. There are 61 homozygotes in gnomad4. There are 1590 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 61 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FANCD2	NM_001018115.3	c.2702G>T	p.Gly901Val	missense_variant	28/44	ENST00000675286.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FANCD2	ENST00000675286.1	c.2702G>T	p.Gly901Val	missense_variant	28/44		NM_001018115.3	P2

Frequencies

GnomAD3 genomes AF: 0.0221 AC: 3364 AN: 152114 Hom.: 61 Cov.: 32

Gnomad AFR AF: 0.00592

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0234

Gnomad ASJ AF: 0.0222

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00477

Gnomad FIN AF: 0.0249

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0346

Gnomad OTH AF: 0.0182

GnomAD3 exomes AF: 0.0218 AC: 5486 AN: 251444 Hom.: 104 AF XY: 0.0213 AC XY: 2896 AN XY: 135900

Gnomad AFR exome AF: 0.00566

Gnomad AMR exome AF: 0.0176

Gnomad ASJ exome AF: 0.0217

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00457

Gnomad FIN exome AF: 0.0230

Gnomad NFE exome AF: 0.0330

Gnomad OTH exome AF: 0.0280

GnomAD4 exome AF: 0.0307 AC: 44743 AN: 1458970 Hom.: 799 Cov.: 30 AF XY: 0.0300 AC XY: 21751 AN XY: 725924

Gnomad4 AFR exome AF: 0.00470

Gnomad4 AMR exome AF: 0.0183

Gnomad4 ASJ exome AF: 0.0236

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00490

Gnomad4 FIN exome AF: 0.0230

Gnomad4 NFE exome AF: 0.0359

Gnomad4 OTH exome AF: 0.0279

GnomAD4 genome AF: 0.0221 AC: 3364 AN: 152232 Hom.: 61 Cov.: 32 AF XY: 0.0214 AC XY: 1590 AN XY: 74426

Gnomad4 AFR AF: 0.00590

Gnomad4 AMR AF: 0.0234

Gnomad4 ASJ AF: 0.0222

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00477

Gnomad4 FIN AF: 0.0249

Gnomad4 NFE AF: 0.0346

Gnomad4 OTH AF: 0.0180

Alfa AF: 0.0305 Hom.: 148

Bravo AF: 0.0214

TwinsUK AF: 0.0364 AC: 135

ALSPAC AF: 0.0353 AC: 136

ESP6500AA AF: 0.00817 AC: 36

ESP6500EA AF: 0.0347 AC: 298

ExAC AF: 0.0220 AC: 2673

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.0277

EpiControl AF: 0.0308

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2 Other:1

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

Fanconi anemia complementation group D2 Benign:2

Benign, 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 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, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 23, 2023	See Variant Classification Assertion Criteria. -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Fanconi anemia Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Hereditary breast ovarian cancer syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

National Health Laboratory Service, Universitas Academic Hospital and University of the Free State

Apr 19, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.48
Cadd	Benign	19
Dann	Benign	0.96
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.15
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.75	T;T;.
MetaRNN	Benign	0.0039	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N;N;N
MutationTaster	Benign	0.94	D;D;D;D
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.7	N;N;N
REVEL	Benign	0.041
Sift	Benign	0.21	T;T;T
Sift4G	Benign	0.093	T;T;T
Polyphen		0.13	.;B;B
Vest4		0.20
MPC		0.22
ClinPred		0.022	T
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.11
gMVP		0.15

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

Other links and lift over

dbSNP: rs35495399; hg19: chr3-10115033; COSMIC: COSV55033803; COSMIC: COSV55033803;