3-10043446-C-G

Position:

• chr3-10043446-C-G

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.990-38C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.174 in 1,510,920 control chromosomes in the GnomAD database, including 25,916 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (5025 hom., cov: 32)
  • Exomes 𝑓: 0.17 (20891 hom.)
• Consequence: FANCD2 NM_001018115.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.925

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=-0.88).
• BP6: Variant 3-10043446-C-G is Benign according to our data. Variant chr3-10043446-C-G is described in ClinVar as [Benign]. Clinvar id is 257088.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.415 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FANCD2	NM_001018115.3	c.990-38C>G		intron_variant		ENST00000675286.1	NP_001018125.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FANCD2	ENST00000675286.1	c.990-38C>G		intron_variant			NM_001018115.3	ENSP00000502379.1

Frequencies

GnomAD3 genomes AF: 0.226 AC: 34328 AN: 151836 Hom.: 5019 Cov.: 32

Gnomad AFR AF: 0.420

Gnomad AMI AF: 0.270

Gnomad AMR AF: 0.156

Gnomad ASJ AF: 0.151

Gnomad EAS AF: 0.0654

Gnomad SAS AF: 0.162

Gnomad FIN AF: 0.117

Gnomad MID AF: 0.143

Gnomad NFE AF: 0.162

Gnomad OTH AF: 0.194

GnomAD3 exomes AF: 0.167 AC: 41368 AN: 247316 Hom.: 4140 AF XY: 0.165 AC XY: 22220 AN XY: 134314

Gnomad AFR exome AF: 0.432

Gnomad AMR exome AF: 0.157

Gnomad ASJ exome AF: 0.158

Gnomad EAS exome AF: 0.0653

Gnomad SAS exome AF: 0.177

Gnomad FIN exome AF: 0.120

Gnomad NFE exome AF: 0.158

Gnomad OTH exome AF: 0.159

GnomAD4 exome AF: 0.168 AC: 228455 AN: 1358966 Hom.: 20891 Cov.: 21 AF XY: 0.168 AC XY: 114340 AN XY: 682076

Gnomad4 AFR exome AF: 0.429

Gnomad4 AMR exome AF: 0.162

Gnomad4 ASJ exome AF: 0.157

Gnomad4 EAS exome AF: 0.0566

Gnomad4 SAS exome AF: 0.180

Gnomad4 FIN exome AF: 0.124

Gnomad4 NFE exome AF: 0.166

Gnomad4 OTH exome AF: 0.173

GnomAD4 genome AF: 0.226 AC: 34364 AN: 151954 Hom.: 5025 Cov.: 32 AF XY: 0.220 AC XY: 16368 AN XY: 74270

Gnomad4 AFR AF: 0.420

Gnomad4 AMR AF: 0.155

Gnomad4 ASJ AF: 0.151

Gnomad4 EAS AF: 0.0654

Gnomad4 SAS AF: 0.163

Gnomad4 FIN AF: 0.117

Gnomad4 NFE AF: 0.162

Gnomad4 OTH AF: 0.194

Alfa AF: 0.113 Hom.: 224

Bravo AF: 0.240

Asia WGS AF: 0.125 AC: 438 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 provided Benign:2

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

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

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	-0.88
CADD	Benign	3.8
DANN	Benign	0.53

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs9809061; hg19: chr3-10085130;