rs2272123

Variant names:

• chr3-10098431-G-A
• rs2272123
• NM_001018115.3:c.4186-289G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001018115.3(FANCD2):​c.4186-289G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.208 in 151,856 control chromosomes in the GnomAD database, including 3,963 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.21 (3963 hom., cov: 32)
• Consequence: FANCD2 NM_001018115.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.355
• Publications: 14 publications found

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]

FANCD2OS (HGNC:28623): (FANCD2 opposite strand) This gene encodes a conserved protein of unknown function. [provided by RefSeq, Jan 2013]

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 3-10098431-G-A is Benign according to our data. Variant chr3-10098431-G-A is described in ClinVar as [Benign]. Clinvar id is 1270020.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.349 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FANCD2	NM_001018115.3	c.4186-289G>A		intron_variant	Intron 42 of 43	ENST00000675286.1	NP_001018125.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FANCD2	ENST00000675286.1	c.4186-289G>A		intron_variant	Intron 42 of 43		NM_001018115.3	ENSP00000502379.1

Frequencies

GnomAD3 genomes AF: 0.208 AC: 31492 AN: 151738 Hom.: 3956 Cov.: 32

Gnomad AFR AF: 0.354

Gnomad AMI AF: 0.269

Gnomad AMR AF: 0.153

Gnomad ASJ AF: 0.151

Gnomad EAS AF: 0.0650

Gnomad SAS AF: 0.159

Gnomad FIN AF: 0.116

Gnomad MID AF: 0.137

Gnomad NFE AF: 0.162

Gnomad OTH AF: 0.179

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.208 AC: 31519 AN: 151856 Hom.: 3963 Cov.: 32 AF XY: 0.202 AC XY: 14981 AN XY: 74232

African (AFR) AF: 0.354 AC: 14667 AN: 41410

American (AMR) AF: 0.153 AC: 2328 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.151 AC: 523 AN: 3472

East Asian (EAS) AF: 0.0650 AC: 336 AN: 5172

South Asian (SAS) AF: 0.160 AC: 770 AN: 4808

European-Finnish (FIN) AF: 0.116 AC: 1226 AN: 10532

Middle Eastern (MID) AF: 0.130 AC: 38 AN: 292

European-Non Finnish (NFE) AF: 0.162 AC: 11011 AN: 67922

Other (OTH) AF: 0.179 AC: 376 AN: 2098

Alfa AF: 0.176 Hom.: 11085

Bravo AF: 0.219

Asia WGS AF: 0.115 AC: 402 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Feb 11, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	1.2
DANN	Benign	0.66
PhyloP100		-0.35
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2272123; hg19: chr3-10140115;