Genetic Variant CDH3:p.Arg503Leu (chr16-68685288-G-T) – ACMG Classification: Likely_pathogenic (8 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2PM5PP3_Strong

The NM_001793.6(CDH3):c.1508G>T(p.Arg503Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,802 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R503H) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

CDH3
NM_001793.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.49

Publications

0 publications found

Variant links:

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)

CDH3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr16-68685288-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 17639.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.947

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH3	NM_001793.6 link	c.1508G>T	p.Arg503Leu	missense_variant	Exon 11 of 16	ENST00000264012.9	NP_001784.2	P22223-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CDH3	ENST00000264012.9 link	c.1508G>T	p.Arg503Leu	missense_variant	Exon 11 of 16	1	NM_001793.6	ENSP00000264012.4	P22223-1
CDH3	ENST00000429102.6 link	c.1508G>T	p.Arg503Leu	missense_variant	Exon 11 of 16	1		ENSP00000398485.2	P22223-2
CDH3	ENST00000542274.5 link	n.*1246G>T		non_coding_transcript_exon_variant	Exon 10 of 15	2		ENSP00000464021.1	J3QR34
CDH3	ENST00000542274.5 link	n.*1246G>T		3_prime_UTR_variant	Exon 10 of 15	2		ENSP00000464021.1	J3QR34

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461802

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727212

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53396

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111956

Other (OTH)

AF:

0.00

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.68

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.26

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.56

D;.

Eigen

Pathogenic

0.86

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.86

D;D

M_CAP

Benign

0.066

MetaRNN

Pathogenic

0.95

D;D

MetaSVM

Uncertain

0.33

MutationAssessor

Pathogenic

3.7

H;H

PhyloP100

7.5

PrimateAI

Benign

0.39

PROVEAN

Pathogenic

-6.9

D;D

REVEL

Uncertain

0.61

Sift

Uncertain

0.0010

D;D

Sift4G

Uncertain

0.0020

D;D

Polyphen

1.0

D;.

Vest4

0.88

MutPred

0.81

Loss of disorder (P = 0.0702);Loss of disorder (P = 0.0702);

MVP

0.87

MPC

0.88

ClinPred

1.0

GERP RS

5.6

Varity_R

0.87

gMVP

0.90

Mutation Taster

=22/78

disease causing

(source)

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

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16-68685288-G-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over