3-10026888-G-T

Variant names:

• chr3-10026888-G-T
• rs3846177
• NM_001018115.3:c.-34+415G>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.-34+415G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.222 in 151,982 control chromosomes in the GnomAD database, including 4,778 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 0.22 (4778 hom., cov: 32)
• Consequence: FANCD2 NM_001018115.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.19
• Publications: 9 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

ENSG00000291078 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.399 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FANCD2	NM_001018115.3	c.-34+415G>T		intron_variant	Intron 1 of 43	ENST00000675286.1	NP_001018125.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FANCD2	ENST00000675286.1	c.-34+415G>T		intron_variant	Intron 1 of 43		NM_001018115.3	ENSP00000502379.1

Frequencies

GnomAD3 genomes AF: 0.222 AC: 33642 AN: 151864 Hom.: 4773 Cov.: 32

Gnomad AFR AF: 0.405

Gnomad AMI AF: 0.272

Gnomad AMR AF: 0.155

Gnomad ASJ AF: 0.151

Gnomad EAS AF: 0.0659

Gnomad SAS AF: 0.161

Gnomad FIN AF: 0.116

Gnomad MID AF: 0.136

Gnomad NFE AF: 0.162

Gnomad OTH AF: 0.191

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

GnomAD4 genome AF: 0.222 AC: 33674 AN: 151982 Hom.: 4778 Cov.: 32 AF XY: 0.216 AC XY: 16028 AN XY: 74286

African (AFR) AF: 0.405 AC: 16759 AN: 41420

American (AMR) AF: 0.154 AC: 2349 AN: 15236

Ashkenazi Jewish (ASJ) AF: 0.151 AC: 523 AN: 3470

East Asian (EAS) AF: 0.0658 AC: 340 AN: 5164

South Asian (SAS) AF: 0.162 AC: 782 AN: 4814

European-Finnish (FIN) AF: 0.116 AC: 1229 AN: 10588

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

European-Non Finnish (NFE) AF: 0.162 AC: 11005 AN: 67982

Other (OTH) AF: 0.191 AC: 403 AN: 2108

Alfa AF: 0.128 Hom.: 303

Bravo AF: 0.235

Asia WGS AF: 0.121 AC: 424 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	6.0
DANN	Benign	0.73
PhyloP100		2.2
PromoterAI		0.030	Neutral
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: rs3846177; hg19: chr3-10068572;