rs34608006

Positions:

• chr3-10065836-G-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.2270-28G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.169 in 1,417,858 control chromosomes in the GnomAD database, including 21,757 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (3260 hom., cov: 32)
  • Exomes 𝑓: 0.17 (18497 hom.)
• Consequence: FANCD2 NM_001018115.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.04

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]

FANCD2 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 3-10065836-G-T is Benign according to our data. Variant chr3-10065836-G-T is described in ClinVar as [Benign]. Clinvar id is 257074.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.303 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FANCD2	NM_001018115.3	c.2270-28G>T		intron_variant		ENST00000675286.1	NP_001018125.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FANCD2	ENST00000675286.1	c.2270-28G>T		intron_variant			NM_001018115.3	ENSP00000502379.1

Frequencies

GnomAD3 genomes AF: 0.194 AC: 29439 AN: 151974 Hom.: 3256 Cov.: 32

Gnomad AFR AF: 0.308

Gnomad AMI AF: 0.268

Gnomad AMR AF: 0.144

Gnomad ASJ AF: 0.151

Gnomad EAS AF: 0.0641

Gnomad SAS AF: 0.164

Gnomad FIN AF: 0.116

Gnomad MID AF: 0.136

Gnomad NFE AF: 0.162

Gnomad OTH AF: 0.169

GnomAD3 exomes AF: 0.160 AC: 39693 AN: 247714 Hom.: 3485 AF XY: 0.160 AC XY: 21468 AN XY: 134032

Gnomad AFR exome AF: 0.319

Gnomad AMR exome AF: 0.154

Gnomad ASJ exome AF: 0.159

Gnomad EAS exome AF: 0.0650

Gnomad SAS exome AF: 0.178

Gnomad FIN exome AF: 0.119

Gnomad NFE exome AF: 0.159

Gnomad OTH exome AF: 0.155

GnomAD4 exome AF: 0.166 AC: 210428 AN: 1265766 Hom.: 18497 Cov.: 18 AF XY: 0.166 AC XY: 106263 AN XY: 639718

Gnomad4 AFR exome AF: 0.320

Gnomad4 AMR exome AF: 0.157

Gnomad4 ASJ exome AF: 0.157

Gnomad4 EAS exome AF: 0.0565

Gnomad4 SAS exome AF: 0.184

Gnomad4 FIN exome AF: 0.123

Gnomad4 NFE exome AF: 0.168

Gnomad4 OTH exome AF: 0.166

GnomAD4 genome AF: 0.194 AC: 29462 AN: 152092 Hom.: 3260 Cov.: 32 AF XY: 0.189 AC XY: 14024 AN XY: 74332

Gnomad4 AFR AF: 0.308

Gnomad4 AMR AF: 0.144

Gnomad4 ASJ AF: 0.151

Gnomad4 EAS AF: 0.0640

Gnomad4 SAS AF: 0.165

Gnomad4 FIN AF: 0.116

Gnomad4 NFE AF: 0.162

Gnomad4 OTH AF: 0.170

Alfa AF: 0.175 Hom.: 469

Bravo AF: 0.203

Asia WGS AF: 0.113 AC: 396 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

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

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	6.7
DANN	Benign	0.70

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: rs34608006; hg19: chr3-10107520;