1-159192730-G-C

Position:

• chr1-159192730-G-C

Variant summary

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

The NM_001127173.3(CADM3):​c.382G>C​(p.Gly128Arg) variant causes a missense, splice region 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. 14/24 in silico tools predict a damaging outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CADM3 NM_001127173.3 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 9.41

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 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, 0.867

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CADM3	NM_001127173.3	c.382G>C	p.Gly128Arg	missense_variant, splice_region_variant	3/9	ENST00000368125.9
CADM3	NM_021189.5	c.484G>C	p.Gly162Arg	missense_variant, splice_region_variant	4/10
CADM3	NM_001346510.2	c.382G>C	p.Gly128Arg	missense_variant, splice_region_variant	3/9
CADM3	XM_024448760.2	c.631G>C	p.Gly211Arg	missense_variant, splice_region_variant	6/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CADM3	ENST00000368125.9	c.382G>C	p.Gly128Arg	missense_variant, splice_region_variant	3/9	1	NM_001127173.3	P2
CADM3	ENST00000368124.8	c.484G>C	p.Gly162Arg	missense_variant, splice_region_variant	4/10	1		A2
CADM3	ENST00000416746.1	c.382G>C	p.Gly128Arg	missense_variant, splice_region_variant	3/7	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Malignant tumor of prostate Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

Science for Life laboratory, Karolinska Institutet

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	34
DANN	Pathogenic	1.0
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.94	D;D;D
MetaRNN	Pathogenic	0.87	D;D;D
MetaSVM	Uncertain	0.22	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.79	T
PROVEAN	Uncertain	-3.6	D;D;D
REVEL	Pathogenic	0.77
Sift	Benign	0.068	T;D;D
Sift4G	Benign	0.16	T;T;D
Polyphen		1.0	D;D;.
Vest4		0.85
MutPred		0.60		.;Gain of MoRF binding (P = 0.0022);Gain of MoRF binding (P = 0.0022);
MVP		0.93
MPC		1.1
ClinPred		0.99	D
GERP RS		5.1
Varity_R		0.73
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.43		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.43		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs193920866; hg19: chr1-159162520; COSMIC: COSV63684755; COSMIC: COSV63684755;