rs200473919

Variant names:

• chr3-10052511-T-A
• rs200473919
• NM_001018115.3:c.1656+14T>A

Your query was ambiguous. Multiple possible variants found:

• chr3-10052511-T-A
• chr3-10052511-T-C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001018115.3(FANCD2):​c.1656+14T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00103 in 1,578,806 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00088 (1 hom., cov: 30)
  • Exomes 𝑓: 0.0010 (5 hom.)
• Consequence: FANCD2 NM_001018115.3 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.405
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• Fanconi anemia complementation group D2

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 3-10052511-T-A is Benign according to our data. Variant chr3-10052511-T-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 257071.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.00105 (1495/1429854) while in subpopulation MID AF = 0.0104 (43/4134). AF 95% confidence interval is 0.00794. There are 5 homozygotes in GnomAdExome4. There are 799 alleles in the male GnomAdExome4 subpopulation. Median coverage is 24. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FANCD2	NM_001018115.3	c.1656+14T>A		intron_variant	Intron 18 of 43	ENST00000675286.1	NP_001018125.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FANCD2	ENST00000675286.1	c.1656+14T>A		intron_variant	Intron 18 of 43		NM_001018115.3	ENSP00000502379.1

Frequencies

GnomAD3 genomes AF: 0.000880 AC: 131 AN: 148836 Hom.: 1 Cov.: 30

Gnomad AFR AF: 0.0000257

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00113

Gnomad ASJ AF: 0.00521

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00252

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00641

Gnomad NFE AF: 0.00108

Gnomad OTH AF: 0.00341

GnomAD2 exomes AF: 0.00126 AC: 317 AN: 250784 AF XY: 0.00137

Gnomad AFR exome AF: 0.0000625

Gnomad AMR exome AF: 0.000810

Gnomad ASJ exome AF: 0.00397

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00157

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00105 AC: 1495 AN: 1429854 Hom.: 5 Cov.: 24 AF XY: 0.00112 AC XY: 799 AN XY: 713270

African (AFR) AF: 0.0000610 AC: 2 AN: 32798

American (AMR) AF: 0.000918 AC: 41 AN: 44668

Ashkenazi Jewish (ASJ) AF: 0.00428 AC: 111 AN: 25950

East Asian (EAS) AF: 0.00 AC: 0 AN: 39554

South Asian (SAS) AF: 0.00216 AC: 185 AN: 85554

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53384

Middle Eastern (MID) AF: 0.0104 AC: 43 AN: 4134

European-Non Finnish (NFE) AF: 0.000960 AC: 1041 AN: 1084658

Other (OTH) AF: 0.00120 AC: 71 AN: 59154

GnomAD4 genome AF: 0.000879 AC: 131 AN: 148952 Hom.: 1 Cov.: 30 AF XY: 0.000934 AC XY: 68 AN XY: 72802

African (AFR) AF: 0.0000256 AC: 1 AN: 39106

American (AMR) AF: 0.00113 AC: 17 AN: 15046

Ashkenazi Jewish (ASJ) AF: 0.00521 AC: 18 AN: 3456

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5174

South Asian (SAS) AF: 0.00252 AC: 12 AN: 4758

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10494

Middle Eastern (MID) AF: 0.00690 AC: 2 AN: 290

European-Non Finnish (NFE) AF: 0.00108 AC: 73 AN: 67644

Other (OTH) AF: 0.00337 AC: 7 AN: 2076

Alfa AF: 0.00103 Hom.: 0

Bravo AF: 0.000752

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Fanconi anemia complementation group D2 Uncertain:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	12
DANN	Benign	0.81
PhyloP100		0.41
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs200473919; hg19: chr3-10094195;