3-10035158-CTTT-CTTTT

Variant names:

• chr3-10035158-C-CT
• rs55973240
• NM_001018115.3:c.378-5dupT

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001018115.3(FANCD2):​c.378-5dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0021 in 1,408,098 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 0.000087 (0 hom., cov: 25)
  • Exomes 𝑓: 0.0023 (0 hom.)
• Consequence: FANCD2 NM_001018115.3 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.334
• Publications: 6 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Variant has high frequency in the NFE (0.00251) population. However there is too low homozygotes in high coverage region: (expected more than 1, got 0).

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.378-5dupT		splice_region intron	N/A	NP_001018125.1	Q9BXW9-2
	FANCD2	NM_033084.6		c.378-5dupT		splice_region intron	N/A	NP_149075.2
	FANCD2	NM_001374254.1		c.378-5dupT		splice_region 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.378-15_378-14insT		intron	N/A	ENSP00000502379.1	Q9BXW9-2
	FANCD2	ENST00000287647.7	TSL:1	c.378-15_378-14insT		intron	N/A	ENSP00000287647.3	Q9BXW9-1
	FANCD2	ENST00000419585.5	TSL:1	c.378-15_378-14insT		intron	N/A	ENSP00000398754.1	Q9BXW9-2

Frequencies

GnomAD3 genomes AF: 0.0000869 AC: 13 AN: 149610 Hom.: 0 Cov.: 25

Gnomad AFR AF: 0.0000244

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000668

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00117

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000200

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000447

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000904 AC: 164 AN: 181326 AF XY: 0.000819

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000775

Gnomad ASJ exome AF: 0.00103

Gnomad EAS exome AF: 0.00136

Gnomad FIN exome AF: 0.00434

Gnomad NFE exome AF: 0.000544

Gnomad OTH exome AF: 0.00116

GnomAD4 exome AF: 0.00235 AC: 2951 AN: 1258384 Hom.: 0 Cov.: 21 AF XY: 0.00215 AC XY: 1347 AN XY: 626724

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000705 AC: 22 AN: 31200

American (AMR) AF: 0.00107 AC: 42 AN: 39264

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 32 AN: 22218

East Asian (EAS) AF: 0.00185 AC: 60 AN: 32446

South Asian (SAS) AF: 0.00112 AC: 84 AN: 74980

European-Finnish (FIN) AF: 0.00243 AC: 108 AN: 44426

Middle Eastern (MID) AF: 0.00116 AC: 6 AN: 5162

European-Non Finnish (NFE) AF: 0.00260 AC: 2485 AN: 957118

Other (OTH) AF: 0.00217 AC: 112 AN: 51570

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000868 AC: 13 AN: 149714 Hom.: 0 Cov.: 25 AF XY: 0.000137 AC XY: 10 AN XY: 73126

African (AFR) AF: 0.0000243 AC: 1 AN: 41068

American (AMR) AF: 0.0000667 AC: 1 AN: 14982

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3426

East Asian (EAS) AF: 0.00117 AC: 6 AN: 5118

South Asian (SAS) AF: 0.00 AC: 0 AN: 4710

European-Finnish (FIN) AF: 0.000200 AC: 2 AN: 9992

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.0000447 AC: 3 AN: 67158

Other (OTH) AF: 0.00 AC: 0 AN: 2072

Alfa AF: 0.00447 Hom.: 220

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.33
BranchPoint Hunter		1.0
Mutation Taster		=100/0	polymorphism

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: rs55973240; hg19: chr3-10076842; COSMIC: COSV55037265; COSMIC: COSV55037265;