NM_001127173.3:c.413A>G

Variant names:

• chr1-159193453-A-G
• rs2102125471
• NM_001127173.3:c.413A>G

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 11P and 1B. PM2 PP2 PP5_Very_Strong BP4

The NM_001127173.3(CADM3):​c.413A>G​(p.Tyr138Cys) 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. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CADM3 NM_001127173.3 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 1.43
• Publications: 2 publications found

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]

CADM3-AS1 (HGNC:40812): (CADM3 antisense RNA 1)

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 1 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 1.6917 (below the threshold of 3.09). Trascript score misZ: 1.5575 (below the threshold of 3.09). GenCC associations: The gene is linked to Charcot-Marie-Tooth disease, axonal, type 2FF.
• PP5: Variant 1-159193453-A-G is Pathogenic according to our data. Variant chr1-159193453-A-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1268234.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.40942085). . Strength limited to SUPPORTING due to the PP5.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001127173.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CADM3	NM_001127173.3	MANE Select	c.413A>G	p.Tyr138Cys	missense	Exon 4 of 9	NP_001120645.1	Q8N126-1
	CADM3	NM_021189.5		c.515A>G	p.Tyr172Cys	missense	Exon 5 of 10	NP_067012.1	Q8N126-2
	CADM3	NM_001346510.2		c.413A>G	p.Tyr138Cys	missense	Exon 4 of 9	NP_001333439.1	Q8N126-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CADM3	ENST00000368125.9	TSL:1 MANE Select	c.413A>G	p.Tyr138Cys	missense	Exon 4 of 9	ENSP00000357107.4	Q8N126-1
	CADM3	ENST00000368124.8	TSL:1	c.515A>G	p.Tyr172Cys	missense	Exon 5 of 10	ENSP00000357106.4	Q8N126-2
	CADM3	ENST00000416746.1	TSL:1	c.413A>G	p.Tyr138Cys	missense	Exon 4 of 7	ENSP00000387802.1	A0A0C4DG09

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Charcot-Marie-Tooth disease, axonal, type 2FF (2)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Uncertain	0.018	T
BayesDel_noAF	Benign	-0.21
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.57	D
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.41	T
MetaSVM	Benign	-0.45	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		1.4
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-3.1	D
REVEL	Uncertain	0.33
Sift	Benign	0.14	T
Sift4G	Benign	0.19	T
Polyphen		1.0	D
Vest4		0.32
MutPred		0.38		Gain of methylation at K139 (P = 0.0267)
MVP		0.58
MPC		1.3
ClinPred		0.98	D
GERP RS		5.1
Varity_R		0.11
gMVP		0.72
Mutation Taster		=71/29	polymorphism

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

Other links and lift over

dbSNP: rs2102125471; hg19: chr1-159163243; COSMIC: COSV63684861; COSMIC: COSV63684861;