rs724159984

Variant names:

• chr16-68681080-TG-T
• rs724159984
• NM_001793.6:c.981delG

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_001793.6(CDH3):​c.981delG​(p.Met327IlefsTer23) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CDH3 NM_001793.6 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: -1.37
• Publications: 3 publications found

Genes affected

CDH3 (HGNC:1762): (cadherin 3) This gene encodes a classical cadherin of the cadherin superfamily. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed to generate the mature glycoprotein. This calcium-dependent cell-cell adhesion protein is comprised of five extracellular cadherin repeats, a transmembrane region and a highly conserved cytoplasmic tail. This gene is located in a gene cluster in a region on the long arm of chromosome 16 that is involved in loss of heterozygosity events in breast and prostate cancer. In addition, aberrant expression of this protein is observed in cervical adenocarcinomas. Mutations in this gene are associated with hypotrichosis with juvenile macular dystrophy and ectodermal dysplasia, ectrodactyly, and macular dystrophy syndrome (EEMS). [provided by RefSeq, Nov 2015]

CDH3 Gene-Disease associations (from GenCC):

• EEM syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, G2P, ClinGen
• congenital hypotrichosis with juvenile macular dystrophy

  Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-68681080-TG-T is Pathogenic according to our data. Variant chr16-68681080-TG-T is described in ClinVar as Pathogenic. ClinVar VariationId is 17638.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001793.6. 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
	CDH3	NM_001793.6	MANE Select	c.981delG	p.Met327IlefsTer23	frameshift	Exon 8 of 16	NP_001784.2
	CDH3	NM_001317195.3		c.981delG	p.Met327IlefsTer23	frameshift	Exon 8 of 16	NP_001304124.1	P22223-2
	CDH3	NM_001317196.2		c.816delG	p.Met272IlefsTer23	frameshift	Exon 7 of 15	NP_001304125.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH3	ENST00000264012.9	TSL:1 MANE Select	c.981delG	p.Met327IlefsTer23	frameshift	Exon 8 of 16	ENSP00000264012.4	P22223-1
	CDH3	ENST00000429102.6	TSL:1	c.981delG	p.Met327IlefsTer23	frameshift	Exon 8 of 16	ENSP00000398485.2	P22223-2
	CDH3	ENST00000914963.1		c.981delG	p.Met327IlefsTer23	frameshift	Exon 8 of 16	ENSP00000585022.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Congenital hypotrichosis with juvenile macular dystrophy (1)
1	-	-	Hypotrichosis with juvenile macular dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-1.4
Mutation Taster		=0/200	disease causing (ClinVar)

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: rs724159984; hg19: chr16-68714983;