NM_001018115.3:c.2860-1690G>C

Variant names:

• chr3-10076391-G-C
• rs6786638
• NM_001018115.3:c.2860-1690G>C

Variant summary

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

The NM_001018115.3(FANCD2):​c.2860-1690G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.196 in 151,768 control chromosomes in the GnomAD database, including 3,346 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 0.20 (3346 hom., cov: 31)
• Consequence: FANCD2 NM_001018115.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.355
• Publications: 12 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=-0.77).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.309 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FANCD2	NM_001018115.3	c.2860-1690G>C		intron_variant	Intron 29 of 43	ENST00000675286.1	NP_001018125.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FANCD2	ENST00000675286.1	c.2860-1690G>C		intron_variant	Intron 29 of 43		NM_001018115.3	ENSP00000502379.1

Frequencies

GnomAD3 genomes AF: 0.196 AC: 29678 AN: 151650 Hom.: 3342 Cov.: 31

Gnomad AFR AF: 0.314

Gnomad AMI AF: 0.269

Gnomad AMR AF: 0.145

Gnomad ASJ AF: 0.150

Gnomad EAS AF: 0.0657

Gnomad SAS AF: 0.165

Gnomad FIN AF: 0.117

Gnomad MID AF: 0.136

Gnomad NFE AF: 0.162

Gnomad OTH AF: 0.170

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

GnomAD4 genome AF: 0.196 AC: 29702 AN: 151768 Hom.: 3346 Cov.: 31 AF XY: 0.191 AC XY: 14138 AN XY: 74164

African (AFR) AF: 0.314 AC: 12979 AN: 41342

American (AMR) AF: 0.145 AC: 2206 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.150 AC: 522 AN: 3470

East Asian (EAS) AF: 0.0656 AC: 339 AN: 5164

South Asian (SAS) AF: 0.165 AC: 796 AN: 4812

European-Finnish (FIN) AF: 0.117 AC: 1228 AN: 10512

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

European-Non Finnish (NFE) AF: 0.162 AC: 10991 AN: 67904

Other (OTH) AF: 0.170 AC: 359 AN: 2108

Alfa AF: 0.0738 Hom.: 89

Bravo AF: 0.205

Asia WGS AF: 0.116 AC: 406 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	9.8
DANN	Benign	0.78
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: rs6786638; hg19: chr3-10118075;