Genetic Variant CADM3:p.Arg178Leu (chr1-159193882-G-T) – ACMG Classification: Benign (-7 pts)

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 1P and 8B. PP2BP4_StrongBS2

The NM_001127173.3(CADM3):c.533G>T(p.Arg178Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,461,468 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. 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. R178H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

CADM3
NM_001127173.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.09

Publications

0 publications found

Variant links:

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 links:

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

CADM3-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -7 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=0.06727141).

BS2

High AC in GnomAdExome4 at 6 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CADM3	NM_001127173.3	MANE Select	c.533G>T	p.Arg178Leu	missense	Exon 5 of 9	NP_001120645.1	Q8N126-1
CADM3	NM_021189.5		c.635G>T	p.Arg212Leu	missense	Exon 6 of 10	NP_067012.1	Q8N126-2
CADM3	NM_001346510.2		c.533G>T	p.Arg178Leu	missense	Exon 5 of 9	NP_001333439.1	Q8N126-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CADM3	ENST00000368125.9	TSL:1 MANE Select	c.533G>T	p.Arg178Leu	missense	Exon 5 of 9	ENSP00000357107.4	Q8N126-1
CADM3	ENST00000368124.8	TSL:1	c.635G>T	p.Arg212Leu	missense	Exon 6 of 10	ENSP00000357106.4	Q8N126-2
CADM3	ENST00000416746.1	TSL:1	c.533G>T	p.Arg178Leu	missense	Exon 5 of 7	ENSP00000387802.1	A0A0C4DG09

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000411

AC:

AN:

1461468

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727026

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33472

American (AMR)

AF:

0.00

AC:

AN:

44702

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26102

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86184

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53396

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00000540

AC:

AN:

1111778

Other (OTH)

AF:

0.00

AC:

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.442

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

-0.041

BayesDel_noAF

Benign

-0.30

CADD

Benign

(source)

DANN

Benign

0.74

DEOGEN2

Benign

0.23

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.096

LIST_S2

Benign

0.78

M_CAP

Benign

0.0085

MetaRNN

Benign

0.067

MetaSVM

Benign

-0.97

MutationAssessor

Benign

-0.76

PhyloP100

1.1

PrimateAI

Benign

0.36

PROVEAN

Benign

0.32

REVEL

Benign

0.25

Sift

Benign

0.36

Sift4G

Benign

0.42

Polyphen

0.0090

Vest4

0.49

MutPred

0.44

Loss of disorder (P = 0.0926)

MVP

0.84

MPC

0.53

ClinPred

0.087

GERP RS

-0.31

Varity_R

0.056

gMVP

0.56

Mutation Taster

=92/8

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over