rs17032278

Positions:

• chr3-10036271-A-G
• chr3-10036271-A-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.439-16A>G variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.167 in 1,597,844 control chromosomes in the GnomAD database, including 23,933 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3423 hom., cov: 29)
  • Exomes 𝑓: 0.16 (20510 hom.)
• Consequence: FANCD2 NM_001018115.3 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.723

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=-0.81).
• BP6: Variant 3-10036271-A-G is Benign according to our data. Variant chr3-10036271-A-G is described in ClinVar as [Benign]. Clinvar id is 257083.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.315 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FANCD2	NM_001018115.3	c.439-16A>G		splice_polypyrimidine_tract_variant, intron_variant		ENST00000675286.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FANCD2	ENST00000675286.1	c.439-16A>G		splice_polypyrimidine_tract_variant, intron_variant			NM_001018115.3	P2

Frequencies

GnomAD3 genomes AF: 0.197 AC: 29682 AN: 151020 Hom.: 3419 Cov.: 29

Gnomad AFR AF: 0.320

Gnomad AMI AF: 0.268

Gnomad AMR AF: 0.145

Gnomad ASJ AF: 0.151

Gnomad EAS AF: 0.0655

Gnomad SAS AF: 0.159

Gnomad FIN AF: 0.115

Gnomad MID AF: 0.136

Gnomad NFE AF: 0.161

Gnomad OTH AF: 0.170

GnomAD3 exomes AF: 0.162 AC: 40657 AN: 251320 Hom.: 3695 AF XY: 0.161 AC XY: 21855 AN XY: 135846

Gnomad AFR exome AF: 0.336

Gnomad AMR exome AF: 0.154

Gnomad ASJ exome AF: 0.159

Gnomad EAS exome AF: 0.0657

Gnomad SAS exome AF: 0.177

Gnomad FIN exome AF: 0.120

Gnomad NFE exome AF: 0.159

Gnomad OTH exome AF: 0.158

GnomAD4 exome AF: 0.163 AC: 236401 AN: 1446706 Hom.: 20510 Cov.: 29 AF XY: 0.163 AC XY: 117783 AN XY: 720572

Gnomad4 AFR exome AF: 0.330

Gnomad4 AMR exome AF: 0.158

Gnomad4 ASJ exome AF: 0.156

Gnomad4 EAS exome AF: 0.0566

Gnomad4 SAS exome AF: 0.179

Gnomad4 FIN exome AF: 0.123

Gnomad4 NFE exome AF: 0.163

Gnomad4 OTH exome AF: 0.165

GnomAD4 genome AF: 0.197 AC: 29707 AN: 151138 Hom.: 3423 Cov.: 29 AF XY: 0.191 AC XY: 14124 AN XY: 73832

Gnomad4 AFR AF: 0.320

Gnomad4 AMR AF: 0.144

Gnomad4 ASJ AF: 0.151

Gnomad4 EAS AF: 0.0654

Gnomad4 SAS AF: 0.160

Gnomad4 FIN AF: 0.115

Gnomad4 NFE AF: 0.161

Gnomad4 OTH AF: 0.170

Alfa AF: 0.176 Hom.: 567

Bravo AF: 0.208

Asia WGS AF: 0.115 AC: 403 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Fanconi anemia complementation group D2 Benign:2

Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Fanconi anemia Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 11, 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	-0.81
CADD	Benign	0.0080
DANN	Benign	0.58
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: rs17032278; hg19: chr3-10077955;