rs200473919

Positions:

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

Variant summary

Our verdict is Benign. Variant got -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

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 -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 id is 257071.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome 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 gnomad4_exome. There are 799 alleles in male gnomad4_exome subpopulation. Median coverage is 24. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FANCD2	NM_001018115.3	c.1656+14T>A		intron_variant		ENST00000675286.1	NP_001018125.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FANCD2	ENST00000675286.1	c.1656+14T>A		intron_variant			NM_001018115.3	ENSP00000502379	P2

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

GnomAD3 exomes AF: 0.00126 AC: 317 AN: 250784 Hom.: 1 AF XY: 0.00137 AC XY: 186 AN XY: 135714

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 SAS exome AF: 0.00186

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

Gnomad4 AFR exome AF: 0.0000610

Gnomad4 AMR exome AF: 0.000918

Gnomad4 ASJ exome AF: 0.00428

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00216

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000960

Gnomad4 OTH exome AF: 0.00120

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

Gnomad4 AFR AF: 0.0000256

Gnomad4 AMR AF: 0.00113

Gnomad4 ASJ AF: 0.00521

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00252

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00108

Gnomad4 OTH AF: 0.00337

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

Uncertain significance, 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, 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

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	12
DANN	Benign	0.81

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: rs200473919; hg19: chr3-10094195;