rs9875081

Variant names:

• chr3-10042251-G-A
• rs9875081
• NM_001018115.3:c.784-308G>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.784-308G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.226 in 152,002 control chromosomes in the GnomAD database, including 5,012 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.23 (5012 hom., cov: 31)
• Consequence: FANCD2 NM_001018115.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.205
• Publications: 15 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]

FANCD2 Gene-Disease associations (from GenCC):

• Fanconi anemia complementation group D2

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BP6: Variant 3-10042251-G-A is Benign according to our data. Variant chr3-10042251-G-A is described in ClinVar as Benign. ClinVar VariationId is 1249236.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.413 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FANCD2	NM_001018115.3	c.784-308G>A		intron_variant	Intron 10 of 43	ENST00000675286.1	NP_001018125.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FANCD2	ENST00000675286.1	c.784-308G>A		intron_variant	Intron 10 of 43		NM_001018115.3	ENSP00000502379.1

Frequencies

GnomAD3 genomes AF: 0.226 AC: 34277 AN: 151884 Hom.: 5006 Cov.: 31

Gnomad AFR AF: 0.419

Gnomad AMI AF: 0.270

Gnomad AMR AF: 0.156

Gnomad ASJ AF: 0.151

Gnomad EAS AF: 0.0661

Gnomad SAS AF: 0.161

Gnomad FIN AF: 0.116

Gnomad MID AF: 0.142

Gnomad NFE AF: 0.162

Gnomad OTH AF: 0.195

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

GnomAD4 genome AF: 0.226 AC: 34313 AN: 152002 Hom.: 5012 Cov.: 31 AF XY: 0.220 AC XY: 16341 AN XY: 74318

African (AFR) AF: 0.419 AC: 17337 AN: 41406

American (AMR) AF: 0.155 AC: 2373 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.151 AC: 523 AN: 3468

East Asian (EAS) AF: 0.0660 AC: 342 AN: 5178

South Asian (SAS) AF: 0.161 AC: 779 AN: 4824

European-Finnish (FIN) AF: 0.116 AC: 1230 AN: 10578

Middle Eastern (MID) AF: 0.129 AC: 38 AN: 294

European-Non Finnish (NFE) AF: 0.162 AC: 11036 AN: 67964

Other (OTH) AF: 0.194 AC: 409 AN: 2104

Alfa AF: 0.186 Hom.: 1281

Bravo AF: 0.240

Asia WGS AF: 0.125 AC: 436 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

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	2.1
DANN	Benign	0.21
PhyloP100		0.20
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs9875081; hg19: chr3-10083935;