rs193920866

chr1-159192730-G-Achr1-159192730-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>A(p.Gly128Arg) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,458,808 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 14/25 in silico tools predict a damaging outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CADM3 NM_001127173.3 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Not reported in ClinVar
• 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, 0.847

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CADM3	NM_001127173.3	c.382G>A	p.Gly128Arg	missense_variant, splice_region_variant	3/9	ENST00000368125.9
CADM3	NM_021189.5	c.484G>A	p.Gly162Arg	missense_variant, splice_region_variant	4/10
CADM3	NM_001346510.2	c.382G>A	p.Gly128Arg	missense_variant, splice_region_variant	3/9
CADM3	XM_024448760.2	c.631G>A	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>A	p.Gly128Arg	missense_variant, splice_region_variant	3/9	1	NM_001127173.3	P2
CADM3	ENST00000368124.8	c.484G>A	p.Gly162Arg	missense_variant, splice_region_variant	4/10	1		A2
CADM3	ENST00000416746.1	c.382G>A	p.Gly128Arg	missense_variant, splice_region_variant	3/7	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000400 AC: 1 AN: 249976 Hom.: 0 AF XY: 0.00000740 AC XY: 1 AN XY: 135050

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1458808 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 725198

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.31	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
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.85	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		0.97	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)		0.27		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.27		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: COSV105294842; COSMIC: COSV105294842;