chr3-10048005-T-G

Variant names:

• chr3-10048005-T-G
• rs35782247
• NM_001018115.3:c.1367T>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001018115.3(FANCD2):​c.1367T>G​(p.Leu456Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00496 in 1,613,156 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L456I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.027 (6 hom., cov: 45)
  • Exomes 𝑓: 0.0027 (3 hom.)
• Consequence: FANCD2 NM_001018115.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:13 O:1
• Conservation: PhyloP100: 3.53

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

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0034121275).
• BP6: Variant 3-10048005-T-G is Benign according to our data. Variant chr3-10048005-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 134311.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-10048005-T-G is described in Lovd as [Benign]. Variant chr3-10048005-T-G is described in Lovd as [Pathogenic].
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0269 (4086/151846) while in subpopulation AFR AF = 0.0942 (3867/41050). AF 95% confidence interval is 0.0917. There are 6 homozygotes in GnomAd4. There are 1964 alleles in the male GnomAd4 subpopulation. Median coverage is 45. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FANCD2	NM_001018115.3	c.1367T>G	p.Leu456Arg	missense_variant	Exon 16 of 44	ENST00000675286.1	NP_001018125.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FANCD2	ENST00000675286.1	c.1367T>G	p.Leu456Arg	missense_variant	Exon 16 of 44		NM_001018115.3	ENSP00000502379.1

Frequencies

GnomAD3 genomes AF: 0.0269 AC: 4080 AN: 151728 Hom.: 7 Cov.: 45

Gnomad AFR AF: 0.0943

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0101

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000220

Gnomad OTH AF: 0.0225

GnomAD2 exomes AF: 0.00705 AC: 1772 AN: 251396 AF XY: 0.00518

Gnomad AFR exome AF: 0.0988

Gnomad AMR exome AF: 0.00382

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000202

Gnomad OTH exome AF: 0.00277

GnomAD4 exome AF: 0.00268 AC: 3921 AN: 1461310 Hom.: 3 Cov.: 63 AF XY: 0.00235 AC XY: 1712 AN XY: 726998

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0945 AC: 3124 AN: 33072

American (AMR) AF: 0.00447 AC: 200 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00402 AC: 23 AN: 5726

European-Non Finnish (NFE) AF: 0.000125 AC: 139 AN: 1111976

Other (OTH) AF: 0.00713 AC: 430 AN: 60344

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0269 AC: 4086 AN: 151846 Hom.: 6 Cov.: 45 AF XY: 0.0264 AC XY: 1964 AN XY: 74262

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0942 AC: 3867 AN: 41050

American (AMR) AF: 0.0101 AC: 155 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000220 AC: 15 AN: 68046

Other (OTH) AF: 0.0222 AC: 47 AN: 2114

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00690 Hom.: 4

ESP6500AA AF: 0.104 AC: 458

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00874 AC: 1061

Asia WGS AF: 0.00982 AC: 34 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000237

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1 Benign:13 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Fanconi anemia complementation group D2 Pathogenic:1 Benign:3

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Sep 12, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 28, 2020

Leiden Open Variation Database

Significance: Pathogenic

Review Status: flagged submission

Collection Method: curation

Curator: Arleen D. Auerbach. Submitter to LOVD: Arleen D. Auerbach. -

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:4

Dec 14, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Apr 25, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 21356188, 27153395, 24728327, 20981092, 17436244) -

not specified Benign:3 Other:1

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 20, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: FANCD2 c.1367T>G (p.Leu456Arg) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.007 in 251396 control chromosomes, predominantly at a frequency of 0.099 within the African or African-American subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 204.49 fold of the estimated maximal expected allele frequency for a pathogenic variant in FANCD2 causing Fanconi Anemia phenotype (0.00048), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, with conflicting interpretation. Based on the evidence outlined above, the variant was classified as benign. -

-

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Fanconi anemia Benign:2

Oct 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 10, 2020

Sema4, Sema4

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Hereditary breast ovarian cancer syndrome Benign:1

Apr 19, 2022

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	0.0056	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.071	.;T;T
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.78	T;T;.
MetaRNN	Benign	0.0034	T;T;T
MetaSVM	Benign	-0.84	T
MutationAssessor	Uncertain	2.6	M;M;M
PhyloP100		3.5
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.99	N;N;N
REVEL	Benign	0.24
Sift	Benign	0.32	T;T;T
Sift4G	Benign	0.35	T;T;T
Polyphen		1.0	.;D;D
Vest4		0.81
MVP		0.84
MPC		0.48
ClinPred		0.025	T
GERP RS		5.7
Varity_R		0.34
gMVP		0.51
Mutation Taster		=98/2	polymorphism (auto)

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: rs35782247; hg19: chr3-10089689; COSMIC: COSV55034964;