rs7615646

chr3-10048089-A-Cchr3-10048089-A-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.1413+38A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.118 in 1,556,388 control chromosomes in the GnomAD database, including 3,047 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (217 hom., cov: 47)
  • Exomes 𝑓: 0.12 (2830 hom.)
• Consequence: FANCD2 NM_001018115.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.402

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=-0.84).
• BP6: Variant 3-10048089-A-C is Benign according to our data. Variant chr3-10048089-A-C is described in ClinVar as [Benign]. Clinvar id is 257067.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.162 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FANCD2	NM_001018115.3	c.1413+38A>C		intron_variant		ENST00000675286.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FANCD2	ENST00000675286.1	c.1413+38A>C		intron_variant			NM_001018115.3	P2

Frequencies

GnomAD3 genomes AF: 0.107 AC: 16222 AN: 150984 Hom.: 217 Cov.: 47

Gnomad AFR AF: 0.165

Gnomad AMI AF: 0.158

Gnomad AMR AF: 0.0914

Gnomad ASJ AF: 0.0891

Gnomad EAS AF: 0.0430

Gnomad SAS AF: 0.106

Gnomad FIN AF: 0.0657

Gnomad MID AF: 0.0769

Gnomad NFE AF: 0.0884

Gnomad OTH AF: 0.0952

GnomAD4 exome AF: 0.119 AC: 166639 AN: 1405282 Hom.: 2830 Cov.: 44 AF XY: 0.117 AC XY: 82302 AN XY: 700940

Gnomad4 AFR exome AF: 0.205

Gnomad4 AMR exome AF: 0.109

Gnomad4 ASJ exome AF: 0.0999

Gnomad4 EAS exome AF: 0.0381

Gnomad4 SAS exome AF: 0.127

Gnomad4 FIN exome AF: 0.0705

Gnomad4 NFE exome AF: 0.122

Gnomad4 OTH exome AF: 0.113

GnomAD4 genome AF: 0.107 AC: 16242 AN: 151106 Hom.: 217 Cov.: 47 AF XY: 0.104 AC XY: 7713 AN XY: 73868

Gnomad4 AFR AF: 0.165

Gnomad4 AMR AF: 0.0911

Gnomad4 ASJ AF: 0.0891

Gnomad4 EAS AF: 0.0429

Gnomad4 SAS AF: 0.107

Gnomad4 FIN AF: 0.0657

Gnomad4 NFE AF: 0.0884

Gnomad4 OTH AF: 0.0951

Alfa AF: 0.159 Hom.: 845

Bravo AF: 0.205

Asia WGS AF: 0.113 AC: 395 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

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

-

- -

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	-0.84
Cadd	Benign	5.5
Dann	Benign	0.53

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs7615646; hg19: chr3-10089773;