chr1-159199798-G-T

Position:

• chr1-159199798-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001127173.3(CADM3):​c.1000G>T​(p.Gly334Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: CADM3 NM_001127173.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:3
• Conservation: PhyloP100: 9.23

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

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.895

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CADM3	NM_001127173.3	c.1000G>T	p.Gly334Cys	missense_variant	8/9	ENST00000368125.9	NP_001120645.1
CADM3-AS1	NR_037870.1	n.1045C>A		non_coding_transcript_exon_variant	3/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CADM3	ENST00000368125.9	c.1000G>T	p.Gly334Cys	missense_variant	8/9	1	NM_001127173.3	ENSP00000357107	P2
CADM3	ENST00000368124.8	c.1102G>T	p.Gly368Cys	missense_variant	9/10	1		ENSP00000357106	A2
CADM3-AS1	ENST00000415675.3	n.1135C>A		non_coding_transcript_exon_variant	3/4	2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, single submitter

Submissions by phenotype

Charcot-Marie-Tooth disease, axonal, type 2FF Uncertain:3

Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, University Hospital Schleswig-Holstein	Feb 01, 2022	- -
Uncertain significance, no assertion criteria provided	clinical testing	Undiagnosed Diseases Network, NIH	Oct 19, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 10, 2021	The CADM3 c.1102G>T p.(Gly368Cys) missense variant, also known as c.1000G>T p.(Gly334Cys), has not, to our knowledge, been reported in the peer-reviewed literature. TThis variant is not observed in version 2.1.1 of the Genome Aggregation Database. In silico tools do not consistently predict a functional consequence of this variant, which is located in the transmembrane domain. Based on the limited evidence, the c.1102G>T p.(Gly368Cys) variant is classified as a variant of uncertain significance for Charcot-Marie-Tooth disease, axonal, type 2FF. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.58	.;D
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Uncertain	0.097	D
MetaRNN	Pathogenic	0.89	D;D
MetaSVM	Uncertain	0.023	D
MutationAssessor	Pathogenic	3.3	.;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-7.5	D;D
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;D
Vest4		0.86
MutPred		0.72		.;Loss of loop (P = 0.0203);
MVP		0.85
MPC		1.3
ClinPred		1.0	D
GERP RS		4.6
Varity_R		0.91
gMVP		0.85

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: chr1-159169588; COSMIC: COSV100929801; COSMIC: COSV100929801;