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

Variant summary

Our verdict is Benign. Variant got -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. 13/20 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

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

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

BS2

High AC in GnomAd4 at 31 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CADM4	NM_145296.2 link	c.10G>A	p.Ala4Thr	missense_variant	Exon 1 of 9	ENST00000222374.3	NP_660339.1	Q8NFZ8
CADM4	XM_005258620.3 link	c.10G>A	p.Ala4Thr	missense_variant	Exon 1 of 8		XP_005258677.1
CADM4	XM_047438387.1 link	c.10G>A	p.Ala4Thr	missense_variant	Exon 1 of 8		XP_047294343.1
CADM4	XM_017026452.1 link	c.7+2182G>A		intron_variant	Intron 1 of 8		XP_016881941.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CADM4	ENST00000222374.3 link	c.10G>A	p.Ala4Thr	missense_variant	Exon 1 of 9	1	NM_145296.2	ENSP00000222374.1		Q8NFZ8

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

GnomAD3 exomes

AF:

0.0000769

AC:

AN:

12996

Hom.:

AF XY:

0.00

AC XY:

AN XY:

7964

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 SAS 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

Gnomad4 AFR exome

AF:

0.000122

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000127

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.000214

AC:

AN:

145112

Hom.:

Cov.:

AF XY:

0.000199

AC XY:

AN XY:

70522

show subpopulations

Gnomad4 AFR

AF:

0.000668

Gnomad4 AMR

AF:

0.000136

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000153

Gnomad4 OTH

AF:

0.000503

Alfa

AF:

0.000142

Hom.:

ExAC

AF:

0.000126

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 26, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.10G>A (p.A4T) alteration is located in exon 1 (coding exon 1) of the CADM4 gene. This alteration results from a G to A substitution at nucleotide position 10, causing the alanine (A) at amino acid position 4 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.47

CADD

Benign

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

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

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.063

gMVP

0.39

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over