Variant 1-159193453-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 12P and 1B. PS1_ModeratePM2PP5_Very_StrongBP4

The NM_001127173.3(CADM3):c.413A>G(p.Tyr138Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.

Frequency

Genomes: not found (cov: 32)

Consequence

CADM3
NM_001127173.3 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 1.43

Variant links:

Genes affected

CADM3 (HGNC:17601): (cell adhesion molecule 3) The protein encoded by this gene is a calcium-independent cell-cell adhesion protein that can form homodimers or heterodimers with other nectin proteins. The encoded protein has both homophilic and heterophilic cell-cell adhesion activity. This gene is reported to be a tumor suppressor gene. [provided by RefSeq, Oct 2016]

CADM3 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PS1

Transcript NM_001127173.3 (CADM3) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 1-159193453-A-G is Pathogenic according to our data. Variant chr1-159193453-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1268234.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.40942085). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
CADM3	NM_001127173.3 linkuse as main transcript	c.413A>G	p.Tyr138Cys	missense_variant	4/9	ENST00000368125.9	NP_001120645.1
CADM3	NM_021189.5 linkuse as main transcript	c.515A>G	p.Tyr172Cys	missense_variant	5/10		NP_067012.1
CADM3	NM_001346510.2 linkuse as main transcript	c.413A>G	p.Tyr138Cys	missense_variant	4/9		NP_001333439.1
CADM3	XM_024448760.2 linkuse as main transcript	c.662A>G	p.Tyr221Cys	missense_variant	7/12		XP_024304528.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CADM3	ENST00000368125.9 linkuse as main transcript	c.413A>G	p.Tyr138Cys	missense_variant	4/9	1	NM_001127173.3	ENSP00000357107	P2	Q8N126-1
CADM3	ENST00000368124.8 linkuse as main transcript	c.515A>G	p.Tyr172Cys	missense_variant	5/10	1		ENSP00000357106	A2	Q8N126-2
CADM3	ENST00000416746.1 linkuse as main transcript	c.413A>G	p.Tyr138Cys	missense_variant	4/7	1		ENSP00000387802

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Charcot-Marie-Tooth disease, axonal, type 2FF

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 16, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 29, 2024	- -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Feb 01, 2024

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 33889941) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.54

BayesDel_addAF

Uncertain

0.018

BayesDel_noAF

Benign

-0.21

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.57

.;D;.

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.90

D;D;D

M_CAP

Benign

0.040

MetaRNN

Benign

0.41

T;T;T

MetaSVM

Benign

-0.45

MutationAssessor

Uncertain

2.0

.;M;.

MutationTaster

Benign

0.98

D;D

PrimateAI

Uncertain

0.56

PROVEAN

Uncertain

-3.1

D;D;D

REVEL

Uncertain

0.33

Sift

Benign

0.14

T;T;T

Sift4G

Benign

0.19

T;T;D

Polyphen

1.0

D;D;.

Vest4

0.32

MutPred

0.38

.;Gain of methylation at K139 (P = 0.0267);Gain of methylation at K139 (P = 0.0267);

MVP

0.58

MPC

1.3

ClinPred

0.98

GERP RS

5.1

Varity_R

0.11

gMVP

0.72

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over