3-10035158-CTTT-CTTTTT

Variant names:

• chr3-10035158-C-CTT
• rs55973240
• NM_001018115.3:c.378-6_378-5dupTT

Variant summary

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

The NM_001018115.3(FANCD2):​c.378-6_378-5dupTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000488 in 1,435,516 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0000067 (0 hom., cov: 25)
  • Exomes 𝑓: 0.0000047 (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: Very rare variant in population databases, with high coverage

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

Frequencies

GnomAD3 genomes AF: 0.00000668 AC: 1 AN: 149632 Hom.: 0 Cov.: 25

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000668

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000165 AC: 3 AN: 181326 AF XY: 0.0000307

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000129

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000467 AC: 6 AN: 1285884 Hom.: 0 Cov.: 21 AF XY: 0.00000469 AC XY: 3 AN XY: 640166

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

African (AFR) AF: 0.00 AC: 0 AN: 31486

American (AMR) AF: 0.0000753 AC: 3 AN: 39816

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22664

East Asian (EAS) AF: 0.00 AC: 0 AN: 33288

South Asian (SAS) AF: 0.00 AC: 0 AN: 76274

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45454

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5250

European-Non Finnish (NFE) AF: 0.00000306 AC: 3 AN: 978942

Other (OTH) AF: 0.00 AC: 0 AN: 52710

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000000000144329), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000668 AC: 1 AN: 149632 Hom.: 0 Cov.: 25 AF XY: 0.00 AC XY: 0 AN XY: 73030

African (AFR) AF: 0.00 AC: 0 AN: 40954

American (AMR) AF: 0.0000668 AC: 1 AN: 14964

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5134

South Asian (SAS) AF: 0.00 AC: 0 AN: 4718

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10000

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67176

Other (OTH) AF: 0.00 AC: 0 AN: 2050

Alfa AF: 0.00 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

Splicing

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

Other links and lift over

dbSNP: rs55973240; hg19: chr3-10076842;