1-159193421-AG-A

Variant names:

• chr1-159193421-AG-A
• NM_001127173.3:c.383delG

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP3

The ENST00000368125.9(CADM3):​c.383-1delG variant causes a splice acceptor, intron 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 (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CADM3 ENST00000368125.9 splice_acceptor, intron
• 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 Likely_pathogenic. Variant got 7 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.11528822 fraction of the gene. Cryptic splice site detected, with MaxEntScore 6.1, offset of 0 (no position change), new splice context is: ccatcccctatccatggcAGaat. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP3: Multiple lines of computational evidence support a deleterious effect 2: max_spliceai, phyloP100way_vertebrate [when was below the threshold]

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CADM3	ENST00000368125.9	c.383-1delG		splice_acceptor_variant, intron_variant	Intron 3 of 8	1	NM_001127173.3	ENSP00000357107.4
CADM3	ENST00000368124.8	c.485-1delG		splice_acceptor_variant, intron_variant	Intron 4 of 9	1		ENSP00000357106.4
CADM3	ENST00000416746.1	c.383-1delG		splice_acceptor_variant, intron_variant	Intron 3 of 6	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

Oct 26, 2022

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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;