rs3864015

Positions:

• chr3-10064460-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.2021+31C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.123 in 110,614 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (0 hom., cov: 33)
  • Exomes 𝑓: 0.082 (3 hom.)
  • Failed GnomAD Quality Control
• Consequence: FANCD2 NM_001018115.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.775

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 3-10064460-C-T is Benign according to our data. Variant chr3-10064460-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 210979.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.174 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FANCD2	NM_001018115.3	c.2021+31C>T		intron_variant		ENST00000675286.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FANCD2	ENST00000675286.1	c.2021+31C>T		intron_variant			NM_001018115.3	P2

Frequencies

GnomAD3 genomes AF: 0.123 AC: 13601 AN: 110536 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.178

Gnomad AMI AF: 0.108

Gnomad AMR AF: 0.103

Gnomad ASJ AF: 0.0981

Gnomad EAS AF: 0.186

Gnomad SAS AF: 0.133

Gnomad FIN AF: 0.0706

Gnomad MID AF: 0.0756

Gnomad NFE AF: 0.102

Gnomad OTH AF: 0.116

GnomAD3 exomes AF: 0.0101 AC: 2204 AN: 217758 Hom.: 1 AF XY: 0.00907 AC XY: 1082 AN XY: 119264

Gnomad AFR exome AF: 0.0219

Gnomad AMR exome AF: 0.00798

Gnomad ASJ exome AF: 0.00299

Gnomad EAS exome AF: 0.0364

Gnomad SAS exome AF: 0.00999

Gnomad FIN exome AF: 0.0104

Gnomad NFE exome AF: 0.00621

Gnomad OTH exome AF: 0.0111

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0823 AC: 69207 AN: 840904 Hom.: 3 Cov.: 26 AF XY: 0.0792 AC XY: 33718 AN XY: 425622

Gnomad4 AFR exome AF: 0.107

Gnomad4 AMR exome AF: 0.0321

Gnomad4 ASJ exome AF: 0.0525

Gnomad4 EAS exome AF: 0.146

Gnomad4 SAS exome AF: 0.0656

Gnomad4 FIN exome AF: 0.0695

Gnomad4 NFE exome AF: 0.0847

Gnomad4 OTH exome AF: 0.0864

GnomAD4 genome AF: 0.123 AC: 13615 AN: 110614 Hom.: 0 Cov.: 33 AF XY: 0.123 AC XY: 6683 AN XY: 54198

Gnomad4 AFR AF: 0.178

Gnomad4 AMR AF: 0.104

Gnomad4 ASJ AF: 0.0981

Gnomad4 EAS AF: 0.186

Gnomad4 SAS AF: 0.133

Gnomad4 FIN AF: 0.0706

Gnomad4 NFE AF: 0.102

Gnomad4 OTH AF: 0.119

Alfa AF: 0.121 Hom.: 0

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Apr 01, 2015

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 19, 2019

- -

Hereditary breast ovarian cancer syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

National Health Laboratory Service, Universitas Academic Hospital and University of the Free State

Apr 19, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	5.8
DANN	Benign	0.82
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs3864015; hg19: chr3-10106144; COSMIC: COSV55045544; COSMIC: COSV55045544;