1-159193453-A-G

Variant names:

• chr1-159193453-A-G
• NM_001127173.3:c.413A>G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 12P and 1B. PS1_Moderate PM2 PP5_Very_Strong BP4

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 the same amino acid substitution has been previously reported as Likely pathogenic in UniProt.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CADM3 NM_001127173.3 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 1.43

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]

ACMG classification

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 rank	MANE	Protein	UniProt
CADM3	NM_001127173.3	c.413A>G	p.Tyr138Cys	missense_variant	Exon 4 of 9	ENST00000368125.9	NP_001120645.1
CADM3	NM_021189.5	c.515A>G	p.Tyr172Cys	missense_variant	Exon 5 of 10		NP_067012.1
CADM3	NM_001346510.2	c.413A>G	p.Tyr138Cys	missense_variant	Exon 4 of 9		NP_001333439.1
CADM3	XM_024448760.2	c.662A>G	p.Tyr221Cys	missense_variant	Exon 7 of 12		XP_024304528.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CADM3	ENST00000368125.9	c.413A>G	p.Tyr138Cys	missense_variant	Exon 4 of 9	1	NM_001127173.3	ENSP00000357107.4
CADM3	ENST00000368124.8	c.515A>G	p.Tyr172Cys	missense_variant	Exon 5 of 10	1		ENSP00000357106.4
CADM3	ENST00000416746.1	c.413A>G	p.Tyr138Cys	missense_variant	Exon 4 of 7	1		ENSP00000387802.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Mar 29, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 16, 2021

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:1

Feb 01, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	T
BayesDel_noAF	Benign	-0.21
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.57	.;D;.
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.41	T;T;T
MetaSVM	Benign	-0.45	T
MutationAssessor	Uncertain	2.0	.;M;.
PrimateAI	Uncertain	0.56	T
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	D
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.

Other links and lift over

hg19: chr1-159163243; COSMIC: COSV63684861; COSMIC: COSV63684861;