3-10094466-C-T

Position:

• chr3-10094466-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.3963+103C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.182 in 949,642 control chromosomes in the GnomAD database, including 19,273 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.24 (5960 hom., cov: 32)
  • Exomes 𝑓: 0.17 (13313 hom.)
• Consequence: FANCD2 NM_001018115.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0590

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]

FANCD2OS (HGNC:28623): (FANCD2 opposite strand) This gene encodes a conserved protein of unknown function. [provided by RefSeq, Jan 2013]

FANCD2 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 3-10094466-C-T is Benign according to our data. Variant chr3-10094466-C-T is described in ClinVar as [Benign]. Clinvar id is 1235228.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.458 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FANCD2	NM_001018115.3	c.3963+103C>T		intron_variant		ENST00000675286.1	NP_001018125.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FANCD2	ENST00000675286.1	c.3963+103C>T		intron_variant			NM_001018115.3	ENSP00000502379.1

Frequencies

GnomAD3 genomes AF: 0.242 AC: 36746 AN: 151852 Hom.: 5953 Cov.: 32

Gnomad AFR AF: 0.464

Gnomad AMI AF: 0.270

Gnomad AMR AF: 0.174

Gnomad ASJ AF: 0.150

Gnomad EAS AF: 0.0905

Gnomad SAS AF: 0.202

Gnomad FIN AF: 0.116

Gnomad MID AF: 0.136

Gnomad NFE AF: 0.162

Gnomad OTH AF: 0.205

GnomAD4 exome AF: 0.171 AC: 136213 AN: 797672 Hom.: 13313 AF XY: 0.171 AC XY: 72467 AN XY: 422938

Gnomad4 AFR exome AF: 0.464

Gnomad4 AMR exome AF: 0.186

Gnomad4 ASJ exome AF: 0.156

Gnomad4 EAS exome AF: 0.0753

Gnomad4 SAS exome AF: 0.210

Gnomad4 FIN exome AF: 0.123

Gnomad4 NFE exome AF: 0.163

Gnomad4 OTH exome AF: 0.180

GnomAD4 genome AF: 0.242 AC: 36778 AN: 151970 Hom.: 5960 Cov.: 32 AF XY: 0.236 AC XY: 17559 AN XY: 74278

Gnomad4 AFR AF: 0.464

Gnomad4 AMR AF: 0.173

Gnomad4 ASJ AF: 0.150

Gnomad4 EAS AF: 0.0903

Gnomad4 SAS AF: 0.202

Gnomad4 FIN AF: 0.116

Gnomad4 NFE AF: 0.162

Gnomad4 OTH AF: 0.205

Alfa AF: 0.0793 Hom.: 98

Bravo AF: 0.259

Asia WGS AF: 0.144 AC: 503 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 11, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	3.8
DANN	Benign	0.48

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: rs7610821; hg19: chr3-10136150;