chr1-159193968-A-G

Position:

• chr1-159193968-A-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001127173.3(CADM3):​c.619A>G​(p.Ile207Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000103 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: CADM3 NM_001127173.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.775

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.08245757).
• BS2: High AC in GnomAdExome4 at 15 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CADM3	NM_001127173.3	c.619A>G	p.Ile207Val	missense_variant	5/9	ENST00000368125.9	NP_001120645.1
CADM3	NM_021189.5	c.721A>G	p.Ile241Val	missense_variant	6/10		NP_067012.1
CADM3	XM_024448760.2	c.868A>G	p.Ile290Val	missense_variant	8/12		XP_024304528.1
CADM3	NM_001346510.2	c.553+66A>G		intron_variant			NP_001333439.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CADM3	ENST00000368125.9	c.619A>G	p.Ile207Val	missense_variant	5/9	1	NM_001127173.3	ENSP00000357107	P2
CADM3	ENST00000368124.8	c.721A>G	p.Ile241Val	missense_variant	6/10	1		ENSP00000357106	A2
CADM3	ENST00000416746.1	c.553+66A>G		intron_variant		1		ENSP00000387802

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1461892 Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6 AN XY: 727246

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000108

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 17, 2023

The c.721A>G (p.I241V) alteration is located in exon 6 (coding exon 6) of the CADM3 gene. This alteration results from a A to G substitution at nucleotide position 721, causing the isoleucine (I) at amino acid position 241 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	9.3
DANN	Benign	0.62
DEOGEN2	Benign	0.24	.;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.084	N
LIST_S2	Benign	0.69	T;T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.082	T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	-0.085	.;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	0.19	N;N
REVEL	Benign	0.19
Sift	Benign	1.0	T;T
Sift4G	Benign	0.95	T;T
Polyphen		0.0030	B;B
Vest4		0.13
MutPred		0.68		.;Gain of disorder (P = 0.079);
MVP		0.50
MPC		0.35
ClinPred		0.55	D
GERP RS		-0.056
Varity_R		0.020
gMVP		0.61

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

LitVar

Other links and lift over

dbSNP: rs1649786188; hg19: chr1-159163758;