chr3-10031130-A-T

Variant names:

• chr3-10031130-A-T
• rs9881859
• NM_001018115.3:c.65-1702A>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001018115.3(FANCD2):​c.65-1702A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.229 in 152,066 control chromosomes in the GnomAD database, including 5,240 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.23 (5240 hom., cov: 32)
• Consequence: FANCD2 NM_001018115.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.147
• Publications: 7 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.427 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001018115.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCD2	NM_001018115.3	MANE Select	c.65-1702A>T		intron	N/A	NP_001018125.1	Q9BXW9-2
	FANCD2	NM_033084.6		c.65-1702A>T		intron	N/A	NP_149075.2
	FANCD2	NM_001374254.1		c.65-1702A>T		intron	N/A	NP_001361183.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCD2	ENST00000675286.1	MANE Select	c.65-1702A>T		intron	N/A	ENSP00000502379.1	Q9BXW9-2
	FANCD2	ENST00000287647.7	TSL:1	c.65-1702A>T		intron	N/A	ENSP00000287647.3	Q9BXW9-1
	FANCD2	ENST00000419585.5	TSL:1	c.65-1702A>T		intron	N/A	ENSP00000398754.1	Q9BXW9-2

Frequencies

GnomAD3 genomes AF: 0.229 AC: 34850 AN: 151948 Hom.: 5236 Cov.: 32

Gnomad AFR AF: 0.432

Gnomad AMI AF: 0.269

Gnomad AMR AF: 0.157

Gnomad ASJ AF: 0.156

Gnomad EAS AF: 0.0657

Gnomad SAS AF: 0.162

Gnomad FIN AF: 0.115

Gnomad MID AF: 0.146

Gnomad NFE AF: 0.162

Gnomad OTH AF: 0.197

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

GnomAD4 genome AF: 0.229 AC: 34886 AN: 152066 Hom.: 5240 Cov.: 32 AF XY: 0.224 AC XY: 16633 AN XY: 74350

African (AFR) AF: 0.432 AC: 17898 AN: 41440

American (AMR) AF: 0.157 AC: 2397 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.156 AC: 542 AN: 3472

East Asian (EAS) AF: 0.0657 AC: 341 AN: 5190

South Asian (SAS) AF: 0.162 AC: 784 AN: 4826

European-Finnish (FIN) AF: 0.115 AC: 1216 AN: 10560

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

European-Non Finnish (NFE) AF: 0.162 AC: 11011 AN: 67980

Other (OTH) AF: 0.197 AC: 415 AN: 2106

Alfa AF: 0.201 Hom.: 482

Bravo AF: 0.244

Asia WGS AF: 0.125 AC: 438 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	4.0
DANN	Benign	0.41
PhyloP100		0.15
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: rs9881859; hg19: chr3-10072814;