NM_001127173.3:c.427C>T

Variant names:

• chr1-159193467-C-T
• rs1021719284
• NM_001127173.3:c.427C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 1P and 5B. PP2 BP4 BS2

The NM_001127173.3(CADM3):​c.427C>T​(p.Arg143Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000048 in 1,459,720 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: CADM3 NM_001127173.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.576
• Publications: 0 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: Likely_benign. The variant received -4 ACMG points.

• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.3425858).
• BS2: High AC in GnomAdExome4 at 7 AD gene.

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.427C>T	p.Arg143Trp	missense	Exon 4 of 9	NP_001120645.1	Q8N126-1
	CADM3	NM_021189.5		c.529C>T	p.Arg177Trp	missense	Exon 5 of 10	NP_067012.1	Q8N126-2
	CADM3	NM_001346510.2		c.427C>T	p.Arg143Trp	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.427C>T	p.Arg143Trp	missense	Exon 4 of 9	ENSP00000357107.4	Q8N126-1
	CADM3	ENST00000368124.8	TSL:1	c.529C>T	p.Arg177Trp	missense	Exon 5 of 10	ENSP00000357106.4	Q8N126-2
	CADM3	ENST00000416746.1	TSL:1	c.427C>T	p.Arg143Trp	missense	Exon 4 of 7	ENSP00000387802.1	A0A0C4DG09

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250580 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000480 AC: 7 AN: 1459720 Hom.: 0 Cov.: 31 AF XY: 0.00000689 AC XY: 5 AN XY: 725766

African (AFR) AF: 0.00 AC: 0 AN: 33434

American (AMR) AF: 0.00 AC: 0 AN: 44650

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26036

East Asian (EAS) AF: 0.00 AC: 0 AN: 39640

South Asian (SAS) AF: 0.00 AC: 0 AN: 86136

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53390

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1110378

Other (OTH) AF: 0.00 AC: 0 AN: 60296

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000468 Hom.: 0

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.0018	T
BayesDel_noAF	Benign	-0.24
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.53	D
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Benign	0.16	N
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.087	D
MetaRNN	Benign	0.34	T
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Benign	1.9	L
PhyloP100		-0.58
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.40
Sift	Uncertain	0.018	D
Sift4G	Uncertain	0.018	D
Polyphen		1.0	D
Vest4		0.28
MutPred		0.53		Loss of disorder (P = 0.013)
MVP		0.51
MPC		1.2
ClinPred		0.88	D
GERP RS		5.1
Varity_R		0.099
gMVP		0.59
Mutation Taster		=77/23	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs1021719284; hg19: chr1-159163257; COSMIC: COSV100930343; COSMIC: COSV100930343;