NM_001127173.3:c.56G>C

Variant names:

• chr1-159171821-G-C
• rs1452208221
• NM_001127173.3:c.56G>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.56G>C​(p.Trp19Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000914 in 1,094,378 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 9.1e-7 (0 hom.)
• Consequence: CADM3 NM_001127173.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.70

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]

AIM2 (HGNC:357): (absent in melanoma 2) AIM2 is a member of the IFI20X /IFI16 family. It plays a putative role in tumorigenic reversion and may control cell proliferation. Interferon-gamma induces expression of AIM2. [provided by RefSeq, Jul 2008]

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=0.18645397).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CADM3	NM_001127173.3	c.56G>C	p.Trp19Ser	missense_variant	Exon 1 of 9	ENST00000368125.9	NP_001120645.1
CADM3	NM_021189.5	c.56G>C	p.Trp19Ser	missense_variant	Exon 1 of 10		NP_067012.1
CADM3	NM_001346510.2	c.56G>C	p.Trp19Ser	missense_variant	Exon 1 of 9		NP_001333439.1
CADM3	XM_024448760.2	c.56G>C	p.Trp19Ser	missense_variant	Exon 1 of 12		XP_024304528.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CADM3	ENST00000368125.9	c.56G>C	p.Trp19Ser	missense_variant	Exon 1 of 9	1	NM_001127173.3	ENSP00000357107.4
CADM3	ENST00000368124.8	c.56G>C	p.Trp19Ser	missense_variant	Exon 1 of 10	1		ENSP00000357106.4
CADM3	ENST00000416746.1	c.56G>C	p.Trp19Ser	missense_variant	Exon 1 of 7	1		ENSP00000387802.1
AIM2	ENST00000695582.1	n.33+15990C>G		intron_variant	Intron 1 of 3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 9.14e-7 AC: 1 AN: 1094378 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 518158

Gnomad4 AFR exome AF: 0.00

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: 0.00

Gnomad4 OTH exome AF: 0.0000226

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Aug 01, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.56G>C (p.W19S) alteration is located in exon 1 (coding exon 1) of the CADM3 gene. This alteration results from a G to C substitution at nucleotide position 56, causing the tryptophan (W) at amino acid position 19 to be replaced by a serine (S). 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	0.087
BayesDel_addAF	Benign	-0.017	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Benign	0.12	.;T;.
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.040
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.57	T;T;T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.19	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.55	N;N;.
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.36	N;N;N
REVEL	Benign	0.13
Sift	Pathogenic	0.0	D;T;T
Sift4G	Pathogenic	0.0	D;T;T
Polyphen		0.0010	B;B;.
Vest4		0.40
MutPred		0.63		Gain of disorder (P = 0.005);Gain of disorder (P = 0.005);Gain of disorder (P = 0.005);
MVP		0.68
MPC		0.70
ClinPred		0.55	D
GERP RS		3.7
Varity_R		0.21
gMVP		0.44

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: rs1452208221; hg19: chr1-159141611;