3-10101265-C-T

Variant names:

• chr3-10101265-C-T
• rs3172417
• ENST00000421731.5:n.*515C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000421731.5(FANCD2):​n.*515C>T variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.377 in 1,598,442 control chromosomes in the GnomAD database, including 122,502 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.30 (8908 hom., cov: 30)
  • Exomes 𝑓: 0.38 (113594 hom.)
• Consequence: FANCD2 ENST00000421731.5 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.25
• Publications: 35 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]

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 3-10101265-C-T is Benign according to our data. Variant chr3-10101265-C-T is described in ClinVar as Benign. ClinVar VariationId is 257063.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.419 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FANCD2	NM_001018115.3	c.*3C>T		3_prime_UTR_variant	Exon 44 of 44	ENST00000675286.1	NP_001018125.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FANCD2	ENST00000675286.1	c.*3C>T		3_prime_UTR_variant	Exon 44 of 44		NM_001018115.3	ENSP00000502379.1

Frequencies

GnomAD3 genomes AF: 0.305 AC: 46212 AN: 151522 Hom.: 8908 Cov.: 30

Gnomad AFR AF: 0.0829

Gnomad AMI AF: 0.471

Gnomad AMR AF: 0.291

Gnomad ASJ AF: 0.477

Gnomad EAS AF: 0.138

Gnomad SAS AF: 0.232

Gnomad FIN AF: 0.472

Gnomad MID AF: 0.437

Gnomad NFE AF: 0.423

Gnomad OTH AF: 0.335

GnomAD2 exomes AF: 0.330 AC: 82734 AN: 250506 AF XY: 0.339

Gnomad AFR exome AF: 0.0692

Gnomad AMR exome AF: 0.209

Gnomad ASJ exome AF: 0.471

Gnomad EAS exome AF: 0.123

Gnomad FIN exome AF: 0.468

Gnomad NFE exome AF: 0.422

Gnomad OTH exome AF: 0.387

GnomAD4 exome AF: 0.385 AC: 556520 AN: 1446806 Hom.: 113594 Cov.: 29 AF XY: 0.383 AC XY: 276099 AN XY: 720590

African (AFR) AF: 0.0696 AC: 2323 AN: 33364

American (AMR) AF: 0.217 AC: 9711 AN: 44676

Ashkenazi Jewish (ASJ) AF: 0.476 AC: 12382 AN: 26032

East Asian (EAS) AF: 0.146 AC: 5784 AN: 39640

South Asian (SAS) AF: 0.234 AC: 20129 AN: 85978

European-Finnish (FIN) AF: 0.461 AC: 24558 AN: 53320

Middle Eastern (MID) AF: 0.407 AC: 2337 AN: 5746

European-Non Finnish (NFE) AF: 0.416 AC: 457330 AN: 1098142

Other (OTH) AF: 0.367 AC: 21966 AN: 59908

GnomAD4 genome AF: 0.305 AC: 46215 AN: 151636 Hom.: 8908 Cov.: 30 AF XY: 0.305 AC XY: 22586 AN XY: 74090

African (AFR) AF: 0.0828 AC: 3422 AN: 41344

American (AMR) AF: 0.291 AC: 4422 AN: 15220

Ashkenazi Jewish (ASJ) AF: 0.477 AC: 1656 AN: 3470

East Asian (EAS) AF: 0.138 AC: 712 AN: 5164

South Asian (SAS) AF: 0.232 AC: 1117 AN: 4810

European-Finnish (FIN) AF: 0.472 AC: 4937 AN: 10464

Middle Eastern (MID) AF: 0.459 AC: 135 AN: 294

European-Non Finnish (NFE) AF: 0.423 AC: 28690 AN: 67862

Other (OTH) AF: 0.332 AC: 697 AN: 2102

Alfa AF: 0.373 Hom.: 41528

Bravo AF: 0.281

Asia WGS AF: 0.208 AC: 723 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jan 10, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: 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	-0.82
CADD	Benign	9.1
DANN	Benign	0.68
PhyloP100		1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	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

Other links and lift over

dbSNP: rs3172417; hg19: chr3-10142949; COSMIC: COSV55031865; COSMIC: COSV55031865;