3-10032962-G-C

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.195G>C(p.Gln65His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00184 in 1,575,196 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0070 (20 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (11 hom.)
• Consequence: FANCD2 NM_001018115.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8 O:1
• Conservation: PhyloP100: 1.06

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=0.008865625).
• BP6: Variant 3-10032962-G-C is Benign according to our data. Variant chr3-10032962-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 134319.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-10032962-G-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00697 (1062/152266) while in subpopulation AFR AF= 0.0225 (936/41536). AF 95% confidence interval is 0.0213. There are 20 homozygotes in gnomad4. There are 525 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 19 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FANCD2	NM_001018115.3	c.195G>C	p.Gln65His	missense_variant	3/44	ENST00000675286.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FANCD2	ENST00000675286.1	c.195G>C	p.Gln65His	missense_variant	3/44		NM_001018115.3	P2

Frequencies

GnomAD3 genomes AF: 0.00696 AC: 1059 AN: 152148 Hom.: 19 Cov.: 32

Gnomad AFR AF: 0.0226

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00341

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00288

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000588

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00268 AC: 671 AN: 250704 Hom.: 6 AF XY: 0.00252 AC XY: 342 AN XY: 135792

Gnomad AFR exome AF: 0.0238

Gnomad AMR exome AF: 0.00234

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.00359

Gnomad SAS exome AF: 0.00297

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000414

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.00129 AC: 1840 AN: 1422930 Hom.: 11 Cov.: 27 AF XY: 0.00128 AC XY: 907 AN XY: 710338

Gnomad4 AFR exome AF: 0.0214

Gnomad4 AMR exome AF: 0.00242

Gnomad4 ASJ exome AF: 0.0000386

Gnomad4 EAS exome AF: 0.00259

Gnomad4 SAS exome AF: 0.00271

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.000466

Gnomad4 OTH exome AF: 0.00284

GnomAD4 genome AF: 0.00697 AC: 1062 AN: 152266 Hom.: 20 Cov.: 32 AF XY: 0.00705 AC XY: 525 AN XY: 74452

Gnomad4 AFR AF: 0.0225

Gnomad4 AMR AF: 0.00340

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00289

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000588

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.00153 Hom.: 2

Bravo AF: 0.00810

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0207 AC: 91

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00303 AC: 368

Asia WGS AF: 0.00376 AC: 13 AN: 3476

EpiCase AF: 0.000654

EpiControl AF: 0.000533

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

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jan 07, 2021	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -

Fanconi anemia Benign:2

Benign, criteria provided, single submitter	curation	Sema4, Sema4	Oct 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	FANCD2: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 04, 2017	- -

Fanconi anemia complementation group D2 Benign:1

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. -

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	Uncertain	0.39
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.14
Cadd	Benign	23
Dann	Uncertain	1.0
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.88	D;D;.;D
MetaRNN	Benign	0.0089	T;T;T;T
MetaSVM	Benign	-0.80	T
MutationAssessor	Uncertain	2.6	M;M;M;M
MutationTaster	Benign	0.79	N;N;N;N;N
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-2.9	D;D;D;D
REVEL	Benign	0.18
Sift	Uncertain	0.017	D;D;D;D
Sift4G	Uncertain	0.011	D;D;D;D
Polyphen		1.0	.;D;D;D
Vest4		0.54
MutPred		0.10		Loss of helix (P = 0.079);Loss of helix (P = 0.079);Loss of helix (P = 0.079);Loss of helix (P = 0.079);
MVP		0.75
MPC		0.28
ClinPred		0.037	T
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.38
gMVP		0.27

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: rs36084488; hg19: chr3-10074646;