NM_001793.6:c.2003-547G>A

Variant names:

• chr16-68694708-G-A
• rs3785133
• NM_001793.6:c.2003-547G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001793.6(CDH3):​c.2003-547G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.564 in 151,748 control chromosomes in the GnomAD database, including 24,427 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.56 (24427 hom., cov: 31)
• Consequence: CDH3 NM_001793.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.171
• Publications: 12 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: G2P, ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
• congenital hypotrichosis with juvenile macular dystrophy

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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.608 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH3	NM_001793.6	c.2003-547G>A		intron_variant	Intron 13 of 15	ENST00000264012.9	NP_001784.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH3	ENST00000264012.9	c.2003-547G>A		intron_variant	Intron 13 of 15	1	NM_001793.6	ENSP00000264012.4

Frequencies

GnomAD3 genomes AF: 0.564 AC: 85546 AN: 151632 Hom.: 24424 Cov.: 31

Gnomad AFR AF: 0.499

Gnomad AMI AF: 0.691

Gnomad AMR AF: 0.513

Gnomad ASJ AF: 0.565

Gnomad EAS AF: 0.501

Gnomad SAS AF: 0.548

Gnomad FIN AF: 0.605

Gnomad MID AF: 0.630

Gnomad NFE AF: 0.613

Gnomad OTH AF: 0.570

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.564 AC: 85589 AN: 151748 Hom.: 24427 Cov.: 31 AF XY: 0.560 AC XY: 41498 AN XY: 74120

African (AFR) AF: 0.498 AC: 20594 AN: 41340

American (AMR) AF: 0.513 AC: 7817 AN: 15236

Ashkenazi Jewish (ASJ) AF: 0.565 AC: 1958 AN: 3468

East Asian (EAS) AF: 0.501 AC: 2579 AN: 5150

South Asian (SAS) AF: 0.548 AC: 2639 AN: 4814

European-Finnish (FIN) AF: 0.605 AC: 6338 AN: 10468

Middle Eastern (MID) AF: 0.622 AC: 183 AN: 294

European-Non Finnish (NFE) AF: 0.613 AC: 41654 AN: 67968

Other (OTH) AF: 0.571 AC: 1200 AN: 2102

Alfa AF: 0.584 Hom.: 10293

Bravo AF: 0.554

Asia WGS AF: 0.493 AC: 1717 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.32
DANN	Benign	0.56
PhyloP100		-0.17
Mutation Taster		=100/0	polymorphism (auto)

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: rs3785133; hg19: chr16-68728611;