NM_001127173.3:c.523G>C

Variant names:

• chr1-159193872-G-C
• rs751691830
• NM_001127173.3:c.523G>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.523G>C​(p.Glu175Gln) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,210 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. 1/1 splice prediction tools predict no significant impact on normal splicing. 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. E175K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CADM3 NM_001127173.3 missense, splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.10

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=0.13069436).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CADM3	NM_001127173.3	c.523G>C	p.Glu175Gln	missense_variant, splice_region_variant	Exon 5 of 9	ENST00000368125.9	NP_001120645.1
CADM3	NM_021189.5	c.625G>C	p.Glu209Gln	missense_variant, splice_region_variant	Exon 6 of 10		NP_067012.1
CADM3	NM_001346510.2	c.523G>C	p.Glu175Gln	missense_variant, splice_region_variant	Exon 5 of 9		NP_001333439.1
CADM3	XM_024448760.2	c.772G>C	p.Glu258Gln	missense_variant, splice_region_variant	Exon 8 of 12		XP_024304528.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CADM3	ENST00000368125.9	c.523G>C	p.Glu175Gln	missense_variant, splice_region_variant	Exon 5 of 9	1	NM_001127173.3	ENSP00000357107.4
CADM3	ENST00000368124.8	c.625G>C	p.Glu209Gln	missense_variant, splice_region_variant	Exon 6 of 10	1		ENSP00000357106.4
CADM3	ENST00000416746.1	c.523G>C	p.Glu175Gln	missense_variant, splice_region_variant	Exon 5 of 7	1		ENSP00000387802.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000798 AC: 2 AN: 250506 Hom.: 0 AF XY: 0.00000739 AC XY: 1 AN XY: 135326

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

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: 6.84e-7 AC: 1 AN: 1461210 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726884

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: 0.00

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	Benign	0.073
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	22
DANN	Benign	0.95
DEOGEN2	Benign	0.29	.;T;.
Eigen	Benign	-0.11
Eigen_PC	Benign	0.022
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.86	D;D;T
M_CAP	Benign	0.0084	T
MetaRNN	Benign	0.13	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.3	.;L;.
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.37	N;N;N
REVEL	Benign	0.11
Sift	Benign	0.56	T;T;T
Sift4G	Benign	0.52	T;T;T
Polyphen		0.30	B;P;.
Vest4		0.21
MutPred		0.34		.;Loss of catalytic residue at E175 (P = 0.0054);Loss of catalytic residue at E175 (P = 0.0054);
MVP		0.70
MPC		0.44
ClinPred		0.16	T
GERP RS		4.1
Varity_R		0.091
gMVP		0.48

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: rs751691830; hg19: chr1-159163662;