3-10035158-CTTT-CTT

Position:

• chr3-10035158-CTTT-CTT

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BS1

The NM_001018115.3(FANCD2):​c.378-5delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00513 in 1,361,364 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 25)
  • Exomes 𝑓: 0.0058 (0 hom.)
• Consequence: FANCD2 NM_001018115.3 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.334

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.00575 (6972/1211700) while in subpopulation AMR AF= 0.00722 (266/36834). AF 95% confidence interval is 0.00651. There are 0 homozygotes in gnomad4_exome. There are 3385 alleles in male gnomad4_exome subpopulation. Median coverage is 21. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FANCD2	NM_001018115.3	c.378-5delT		splice_region_variant, intron_variant		ENST00000675286.1	NP_001018125.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FANCD2	ENST00000675286.1	c.378-5delT		splice_region_variant, intron_variant			NM_001018115.3	ENSP00000502379.1

Frequencies

GnomAD3 genomes AF: 0.000114 AC: 17 AN: 149560 Hom.: 0 Cov.: 25

Gnomad AFR AF: 0.0000244

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000267

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000601

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000894

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00594 AC: 1077 AN: 181326 Hom.: 0 AF XY: 0.00615 AC XY: 601 AN XY: 97648

Gnomad AFR exome AF: 0.000472

Gnomad AMR exome AF: 0.00913

Gnomad ASJ exome AF: 0.00324

Gnomad EAS exome AF: 0.00591

Gnomad SAS exome AF: 0.0115

Gnomad FIN exome AF: 0.00739

Gnomad NFE exome AF: 0.00448

Gnomad OTH exome AF: 0.00837

GnomAD4 exome AF: 0.00575 AC: 6972 AN: 1211700 Hom.: 0 Cov.: 21 AF XY: 0.00562 AC XY: 3385 AN XY: 602640

Gnomad4 AFR exome AF: 0.00248

Gnomad4 AMR exome AF: 0.00722

Gnomad4 ASJ exome AF: 0.00464

Gnomad4 EAS exome AF: 0.00449

Gnomad4 SAS exome AF: 0.00613

Gnomad4 FIN exome AF: 0.00716

Gnomad4 NFE exome AF: 0.00579

Gnomad4 OTH exome AF: 0.00575

GnomAD4 genome AF: 0.000114 AC: 17 AN: 149664 Hom.: 0 Cov.: 25 AF XY: 0.000123 AC XY: 9 AN XY: 73100

Gnomad4 AFR AF: 0.0000244

Gnomad4 AMR AF: 0.000267

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000601

Gnomad4 NFE AF: 0.0000894

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BranchPoint Hunter		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs55973240; hg19: chr3-10076842;