rs724159985

Positions:

• chr16-68679935-AG-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001793.6(CDH3):​c.830del​(p.Gly277AlafsTer20) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000752 in 1,461,856 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: CDH3 NM_001793.6 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 10.0

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 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 16-68679935-AG-A is Pathogenic according to our data. Variant chr16-68679935-AG-A is described in ClinVar as [Pathogenic]. Clinvar id is 17641.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-68679935-AG-A is described in Lovd as [Pathogenic]. Variant chr16-68679935-AG-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDH3	NM_001793.6	c.830del	p.Gly277AlafsTer20	frameshift_variant	7/16	ENST00000264012.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH3	ENST00000264012.9	c.830del	p.Gly277AlafsTer20	frameshift_variant	7/16	1	NM_001793.6	P1
CDH3	ENST00000429102.6	c.830del	p.Gly277AlafsTer20	frameshift_variant	7/16	1
CDH3	ENST00000542274.5	c.*568del		3_prime_UTR_variant, NMD_transcript_variant	6/15	2
CDH3	ENST00000569036.2	c.*127del		3_prime_UTR_variant, NMD_transcript_variant	3/5	4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000752 AC: 11 AN: 1461856 Hom.: 0 Cov.: 34 AF XY: 0.00000825 AC XY: 6 AN XY: 727230

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000809

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Congenital hypotrichosis with juvenile macular dystrophy Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Breakthrough Genomics, Breakthrough Genomics	-	This variant was previously reported in patients diagnosed with hypotrichosis with juvenile macular dystrophy (HJMD) and EEM syndrome [PMID: 30607044, 31560841, 15805154, 14708629]. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Aug 19, 2021	ACMG classification criteria: PVS1 very strong, PS4 moderate, PM2 moderate, PM3 moderate -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	Dec 17, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jul 17, 2023	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 17641). This sequence change creates a premature translational stop signal (p.Gly277Alafs*20) in the CDH3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CDH3 are known to be pathogenic (PMID: 15805154, 27386845, 29620724). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with CDH3-related conditions (PMID: 14708629, 28041643, 32581362). This variant is also known as 829delG. -

EEM syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 01, 2005

- -

Macular dystrophy Pathogenic:1

Pathogenic, no assertion criteria provided

research

NIHR Bioresource Rare Diseases, University of Cambridge

Jan 01, 2015

- -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs724159985; hg19: chr16-68713838;