NM_001018115.3:c.378-5delT

Variant names:

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

Variant summary

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

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. Variant has been reported in ClinVar as (no stars).

• 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
• 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 AMR (0.00651) population. However there is too low homozygotes in high coverage region: (expected more than 8, 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.378-5delT		splice_region intron	N/A	NP_001018125.1	Q9BXW9-2
	FANCD2	NM_033084.6		c.378-5delT		splice_region intron	N/A	NP_149075.2
	FANCD2	NM_001374254.1		c.378-5delT		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.378-14delT		intron	N/A	ENSP00000502379.1	Q9BXW9-2
	FANCD2	ENST00000287647.7	TSL:1	c.378-14delT		intron	N/A	ENSP00000287647.3	Q9BXW9-1
	FANCD2	ENST00000419585.5	TSL:1	c.378-14delT		intron	N/A	ENSP00000398754.1	Q9BXW9-2

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

GnomAD2 exomes AF: 0.00594 AC: 1077 AN: 181326 AF XY: 0.00615

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 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

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

African (AFR) AF: 0.00248 AC: 76 AN: 30676

American (AMR) AF: 0.00722 AC: 266 AN: 36834

Ashkenazi Jewish (ASJ) AF: 0.00464 AC: 97 AN: 20894

East Asian (EAS) AF: 0.00449 AC: 135 AN: 30044

South Asian (SAS) AF: 0.00613 AC: 433 AN: 70678

European-Finnish (FIN) AF: 0.00716 AC: 303 AN: 42316

Middle Eastern (MID) AF: 0.00337 AC: 17 AN: 5040

European-Non Finnish (NFE) AF: 0.00579 AC: 5361 AN: 925788

Other (OTH) AF: 0.00575 AC: 284 AN: 49430

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

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

African (AFR) AF: 0.0000244 AC: 1 AN: 41062

American (AMR) AF: 0.000267 AC: 4 AN: 14974

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3422

East Asian (EAS) AF: 0.00 AC: 0 AN: 5120

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

European-Finnish (FIN) AF: 0.000601 AC: 6 AN: 9986

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

European-Non Finnish (NFE) AF: 0.0000894 AC: 6 AN: 67132

Other (OTH) AF: 0.00 AC: 0 AN: 2070

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000166269), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0311 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)		0.070		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: COSV55043437; COSMIC: COSV55043437;