rs3895942

Positions:

• chr3-10067061-G-C
• chr3-10067061-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001018115.3(FANCD2):​c.2386-148G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.177 in 641,450 control chromosomes in the GnomAD database, including 12,306 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.22 (4901 hom., cov: 32)
  • Exomes 𝑓: 0.16 (7405 hom.)
• Consequence: FANCD2 NM_001018115.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0580

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 3-10067061-G-C is Benign according to our data. Variant chr3-10067061-G-C is described in ClinVar as [Benign]. Clinvar id is 1259537.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.408 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FANCD2	NM_001018115.3	c.2386-148G>C		intron_variant		ENST00000675286.1	NP_001018125.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FANCD2	ENST00000675286.1	c.2386-148G>C		intron_variant			NM_001018115.3	ENSP00000502379.1

Frequencies

GnomAD3 genomes AF: 0.224 AC: 34042 AN: 151814 Hom.: 4896 Cov.: 32

Gnomad AFR AF: 0.414

Gnomad AMI AF: 0.269

Gnomad AMR AF: 0.155

Gnomad ASJ AF: 0.151

Gnomad EAS AF: 0.0655

Gnomad SAS AF: 0.166

Gnomad FIN AF: 0.117

Gnomad MID AF: 0.142

Gnomad NFE AF: 0.162

Gnomad OTH AF: 0.193

GnomAD4 exome AF: 0.163 AC: 79740 AN: 489518 Hom.: 7405 AF XY: 0.163 AC XY: 43117 AN XY: 263736

Gnomad4 AFR exome AF: 0.410

Gnomad4 AMR exome AF: 0.163

Gnomad4 ASJ exome AF: 0.156

Gnomad4 EAS exome AF: 0.0549

Gnomad4 SAS exome AF: 0.186

Gnomad4 FIN exome AF: 0.123

Gnomad4 NFE exome AF: 0.162

Gnomad4 OTH exome AF: 0.173

GnomAD4 genome AF: 0.224 AC: 34075 AN: 151932 Hom.: 4901 Cov.: 32 AF XY: 0.219 AC XY: 16229 AN XY: 74248

Gnomad4 AFR AF: 0.413

Gnomad4 AMR AF: 0.155

Gnomad4 ASJ AF: 0.151

Gnomad4 EAS AF: 0.0655

Gnomad4 SAS AF: 0.166

Gnomad4 FIN AF: 0.117

Gnomad4 NFE AF: 0.162

Gnomad4 OTH AF: 0.193

Alfa AF: 0.185 Hom.: 391

Bravo AF: 0.238

Asia WGS AF: 0.125 AC: 438 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

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	-0.92
CADD	Benign	2.6
DANN	Benign	0.74

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: rs3895942; hg19: chr3-10108745;