chr1-159192718-G-C

Variant names:

• chr1-159192718-G-C
• rs369946971
• NM_001127173.3:c.370G>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_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. 14/21 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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.995

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18595302).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CADM3	NM_001127173.3	c.370G>C	p.Val124Leu	missense_variant	Exon 3 of 9	ENST00000368125.9	NP_001120645.1
CADM3	NM_021189.5	c.472G>C	p.Val158Leu	missense_variant	Exon 4 of 10		NP_067012.1
CADM3	NM_001346510.2	c.370G>C	p.Val124Leu	missense_variant	Exon 3 of 9		NP_001333439.1
CADM3	XM_024448760.2	c.619G>C	p.Val207Leu	missense_variant	Exon 6 of 12		XP_024304528.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CADM3	ENST00000368125.9	c.370G>C	p.Val124Leu	missense_variant	Exon 3 of 9	1	NM_001127173.3	ENSP00000357107.4
CADM3	ENST00000368124.8	c.472G>C	p.Val158Leu	missense_variant	Exon 4 of 10	1		ENSP00000357106.4
CADM3	ENST00000416746.1	c.370G>C	p.Val124Leu	missense_variant	Exon 3 of 7	1		ENSP00000387802.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251006 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135646

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 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 Cov.: 31

GnomAD4 genome Cov.: 32

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	21
DANN	Benign	0.72
DEOGEN2	Benign	0.088	.;T;.
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.15
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.85	D;D;D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.19	T;T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	0.12	.;N;.
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	0.24	N;N;N
REVEL	Benign	0.24
Sift	Benign	1.0	T;T;T
Sift4G	Benign	0.64	T;T;T
Polyphen		0.97	D;B;.
Vest4		0.38
MVP		0.73
MPC		0.85
ClinPred		0.16	T
GERP RS		4.2
Varity_R		0.19
gMVP		0.69

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

LitVar

Other links and lift over

dbSNP: rs369946971; hg19: chr1-159162508;