Genetic Variant CADM3:p.Val124Leu (chr1-159192718-G-C) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate

The NM_001127173.3(CADM3):c.370G>C(p.Val124Leu) 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. 15/22 in silico tools predict a benign 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. V124I) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

CADM3
NM_001127173.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.995

Publications

0 publications found

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:

CADM3-AS1 (HGNC:40812): (CADM3 antisense RNA 1)

CADM3-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 1 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 1.6917 (below the threshold of 3.09). Trascript score misZ: 1.5575 (below the threshold of 3.09). GenCC associations: The gene is linked to Charcot-Marie-Tooth disease, axonal, type 2FF.

BP4

Computational evidence support a benign effect (MetaRNN=0.18595302).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001127173.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CADM3	NM_001127173.3	MANE Select	c.370G>C	p.Val124Leu	missense	Exon 3 of 9	NP_001120645.1	Q8N126-1
CADM3	NM_021189.5		c.472G>C	p.Val158Leu	missense	Exon 4 of 10	NP_067012.1	Q8N126-2
CADM3	NM_001346510.2		c.370G>C	p.Val124Leu	missense	Exon 3 of 9	NP_001333439.1	Q8N126-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CADM3	ENST00000368125.9	TSL:1 MANE Select	c.370G>C	p.Val124Leu	missense	Exon 3 of 9	ENSP00000357107.4	Q8N126-1
CADM3	ENST00000368124.8	TSL:1	c.472G>C	p.Val158Leu	missense	Exon 4 of 10	ENSP00000357106.4	Q8N126-2
CADM3	ENST00000416746.1	TSL:1	c.370G>C	p.Val124Leu	missense	Exon 3 of 7	ENSP00000387802.1	A0A0C4DG09

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251006

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.63

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.28

CADD

Benign

(source)

DANN

Benign

0.72

DEOGEN2

Benign

0.088

Eigen

Benign

-0.34

Eigen_PC

Benign

-0.15

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.85

M_CAP

Benign

0.017

MetaRNN

Benign

0.19

MetaSVM

Benign

-0.86

MutationAssessor

Benign

0.12

PhyloP100

0.99

PrimateAI

Uncertain

0.63

PROVEAN

Benign

0.24

REVEL

Benign

0.24

Sift

Benign

1.0

Sift4G

Benign

0.64

Polyphen

0.97

Vest4

0.38

MVP

0.73

MPC

0.85

ClinPred

0.16

GERP RS

4.2

Varity_R

0.19

gMVP

0.69

Mutation Taster

=59/41

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over