rs3864017

Positions:

• chr3-10064848-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001018115.3(FANCD2):​c.2141C>T​(p.Pro714Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.149 in 1,536,518 control chromosomes in the GnomAD database, including 14,248 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (1870 hom., cov: 32)
  • Exomes 𝑓: 0.14 (12378 hom.)
• Consequence: FANCD2 NM_001018115.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13 O:1
• Conservation: PhyloP100: -0.0900

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]

FANCD2 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0033615232).
• BP6: Variant 3-10064848-C-T is Benign according to our data. Variant chr3-10064848-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 134315.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-10064848-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.279 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FANCD2	NM_001018115.3	c.2141C>T	p.Pro714Leu	missense_variant	23/44	ENST00000675286.1	NP_001018125.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FANCD2	ENST00000675286.1	c.2141C>T	p.Pro714Leu	missense_variant	23/44		NM_001018115.3	ENSP00000502379.1

Frequencies

GnomAD3 genomes AF: 0.188 AC: 27645 AN: 147016 Hom.: 1866 Cov.: 32

Gnomad AFR AF: 0.284

Gnomad AMI AF: 0.268

Gnomad AMR AF: 0.143

Gnomad ASJ AF: 0.152

Gnomad EAS AF: 0.0626

Gnomad SAS AF: 0.161

Gnomad FIN AF: 0.122

Gnomad MID AF: 0.132

Gnomad NFE AF: 0.163

Gnomad OTH AF: 0.169

GnomAD3 exomes AF: 0.142 AC: 34399 AN: 242424 Hom.: 2024 AF XY: 0.142 AC XY: 18630 AN XY: 131108

Gnomad AFR exome AF: 0.261

Gnomad AMR exome AF: 0.139

Gnomad ASJ exome AF: 0.150

Gnomad EAS exome AF: 0.0524

Gnomad SAS exome AF: 0.162

Gnomad FIN exome AF: 0.113

Gnomad NFE exome AF: 0.141

Gnomad OTH exome AF: 0.142

GnomAD4 exome AF: 0.145 AC: 201031 AN: 1389386 Hom.: 12378 Cov.: 35 AF XY: 0.145 AC XY: 100652 AN XY: 692730

Gnomad4 AFR exome AF: 0.270

Gnomad4 AMR exome AF: 0.146

Gnomad4 ASJ exome AF: 0.148

Gnomad4 EAS exome AF: 0.0514

Gnomad4 SAS exome AF: 0.165

Gnomad4 FIN exome AF: 0.121

Gnomad4 NFE exome AF: 0.144

Gnomad4 OTH exome AF: 0.147

GnomAD4 genome AF: 0.188 AC: 27669 AN: 147132 Hom.: 1870 Cov.: 32 AF XY: 0.184 AC XY: 13178 AN XY: 71752

Gnomad4 AFR AF: 0.284

Gnomad4 AMR AF: 0.143

Gnomad4 ASJ AF: 0.152

Gnomad4 EAS AF: 0.0625

Gnomad4 SAS AF: 0.162

Gnomad4 FIN AF: 0.122

Gnomad4 NFE AF: 0.162

Gnomad4 OTH AF: 0.168

Alfa AF: 0.165 Hom.: 509

ExAC AF: 0.154 AC: 18760

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4 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, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 10, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 12, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 03, 2021	- -

Fanconi anemia complementation group D2 Benign:3

Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
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. -

Fanconi anemia Benign:2

Benign, criteria provided, single submitter	curation	Sema4, Sema4	Dec 09, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 01, 2019	This variant is associated with the following publications: (PMID: 30250602) -

Fanconi anemia complementation group A Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

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	0.061
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	2.1
DANN	Benign	0.46
DEOGEN2	Benign	0.063	.;T;T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.052	N
LIST_S2	Benign	0.25	T;T;.
MetaRNN	Benign	0.0034	T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.0	N;N;N
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-1.7	N;N;N
REVEL	Benign	0.028
Sift	Benign	0.25	T;T;T
Sift4G	Benign	0.23	T;T;T
Polyphen		0.0010	.;B;B
Vest4		0.052
MPC		0.15
ClinPred		0.0018	T
GERP RS		-3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.018
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: rs3864017; hg19: chr3-10106532; COSMIC: COSV55033303;