Genetic Variant CADM4:p.Ala4Thr (chr19-43639781-C-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_145296.2(CADM4):c.10G>A(p.Ala4Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000334 in 1,016,548 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00021 ( 0 hom., cov: 27)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

CADM4
NM_145296.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.08

Publications

0 publications found

Variant links:

Genes affected

CADM4 (HGNC:30825): (cell adhesion molecule 4) Enables vascular endothelial growth factor receptor 2 binding activity. Involved in several processes, including negative regulation of protein phosphorylation; regulation of Rac protein signal transduction; and regulation of wound healing. Located in cell leading edge and cell-cell contact zone. [provided by Alliance of Genome Resources, Apr 2022]

CADM4 links:

ENSG00000308028 (HGNC:):

ENSG00000308028 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0023324788).

BS2

High AC in GnomAd4 at 31 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_145296.2. 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
	CADM4	NM_145296.2	MANE Select	c.10G>A	p.Ala4Thr	missense	Exon 1 of 9	NP_660339.1	Q8NFZ8

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CADM4	ENST00000222374.3	TSL:1 MANE Select	c.10G>A	p.Ala4Thr	missense	Exon 1 of 9	ENSP00000222374.1	Q8NFZ8
CADM4	ENST00000904152.1		c.10G>A	p.Ala4Thr	missense	Exon 1 of 10	ENSP00000574211.1
CADM4	ENST00000904153.1		c.10G>A	p.Ala4Thr	missense	Exon 1 of 9	ENSP00000574212.1

Frequencies

GnomAD3 genomes

AF:

0.000214

AC:

AN:

145112

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000668

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000136

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000153

Gnomad OTH

AF:

0.000503

GnomAD2 exomes

AF:

0.0000769

AC:

AN:

12996

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00562

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000344

AC:

AN:

871436

Hom.:

Cov.:

AF XY:

0.00000486

AC XY:

AN XY:

411160

show subpopulations

African (AFR)

AF:

0.000122

AC:

AN:

16350

American (AMR)

AF:

0.00

AC:

AN:

4160

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

6344

East Asian (EAS)

AF:

0.00

AC:

AN:

4430

South Asian (SAS)

AF:

0.00

AC:

AN:

22808

European-Finnish (FIN)

AF:

0.00

AC:

AN:

1348

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1746

European-Non Finnish (NFE)

AF:

0.00000127

AC:

AN:

785478

Other (OTH)

AF:

0.00

AC:

AN:

28772

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.542

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

AF:

0.000214

AC:

AN:

145112

Hom.:

Cov.:

AF XY:

0.000199

AC XY:

AN XY:

70522

show subpopulations

African (AFR)

AF:

0.000668

AC:

AN:

40424

American (AMR)

AF:

0.000136

AC:

AN:

14662

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3384

East Asian (EAS)

AF:

0.00

AC:

AN:

4962

South Asian (SAS)

AF:

0.00

AC:

AN:

4772

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8246

Middle Eastern (MID)

AF:

0.00

AC:

AN:

308

European-Non Finnish (NFE)

AF:

0.0000153

AC:

AN:

65468

Other (OTH)

AF:

0.000503

AC:

AN:

1988

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.554

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.000142

Hom.:

ExAC

AF:

0.000126

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.47

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.00063

Eigen

Benign

-0.63

Eigen_PC

Benign

-0.53

FATHMM_MKL

Benign

0.18

LIST_S2

Benign

0.48

MetaRNN

Benign

0.0023

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

PhyloP100

2.1

PrimateAI

Uncertain

0.62

PROVEAN

Benign

-0.42

REVEL

Benign

0.048

Sift

Benign

0.053

Sift4G

Pathogenic

0.0

Polyphen

0.030

Vest4

0.15

MutPred

0.38

Gain of phosphorylation at A4 (P = 0.0337)

MVP

0.26

MPC

1.5

ClinPred

0.11

GERP RS

1.5

PromoterAI

-0.072

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.063

gMVP

0.39

Mutation Taster

=86/14

polymorphism

(source)

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

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over