1-159193421-AG-A

Position:

• chr1-159193421-AG-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001127173.3(CADM3):​c.383delG​(p.Gly128fs) variant causes a frameshift, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CADM3 NM_001127173.3 frameshift, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.87

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CADM3	NM_001127173.3	c.383delG	p.Gly128fs	frameshift_variant, splice_region_variant	4/9	ENST00000368125.9	NP_001120645.1
CADM3	NM_021189.5	c.485delG	p.Gly162fs	frameshift_variant, splice_region_variant	5/10		NP_067012.1
CADM3	NM_001346510.2	c.383delG	p.Gly128fs	frameshift_variant, splice_region_variant	4/9		NP_001333439.1
CADM3	XM_024448760.2	c.632delG	p.Gly211fs	frameshift_variant, splice_region_variant	7/12		XP_024304528.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CADM3	ENST00000368125.9	c.383delG	p.Gly128fs	frameshift_variant, splice_region_variant	4/9	1	NM_001127173.3	ENSP00000357107.4
CADM3	ENST00000368124.8	c.485delG	p.Gly162fs	frameshift_variant, splice_region_variant	5/10	1		ENSP00000357106.4
CADM3	ENST00000416746.1	c.383delG	p.Gly128fs	frameshift_variant, splice_region_variant	4/7	1		ENSP00000387802.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Charcot-Marie-Tooth disease, axonal, type 2FF Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Oct 26, 2022

According to in silico predictions, this variant might rather impact splicing and could lead to an in-frame skipping of Exon 4 containing parts of the _x000D_functional C2-type 1 domain. Criteria applied: PVS1_STR, PM2_SUP -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.85		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.60		Position offset: 3
DS_AL_spliceai		0.85		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-159163211;