19-43639781-C-T

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

1
2
15

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]

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
CADM4NM_145296.2 linkc.10G>A p.Ala4Thr missense_variant Exon 1 of 9 ENST00000222374.3 NP_660339.1 Q8NFZ8
CADM4XM_005258620.3 linkc.10G>A p.Ala4Thr missense_variant Exon 1 of 8 XP_005258677.1
CADM4XM_047438387.1 linkc.10G>A p.Ala4Thr missense_variant Exon 1 of 8 XP_047294343.1
CADM4XM_017026452.1 linkc.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
CADM4ENST00000222374.3 linkc.10G>A p.Ala4Thr missense_variant Exon 1 of 9 1 NM_145296.2 ENSP00000222374.1 Q8NFZ8

Frequencies

GnomAD3 genomes
AF:
0.000214
AC:
31
AN:
145112
Hom.:
0
Cov.:
27
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:
1
AN:
12996
Hom.:
0
AF XY:
0.00
AC XY:
0
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:
3
AN:
871436
Hom.:
0
Cov.:
33
AF XY:
0.00000486
AC XY:
2
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:
31
AN:
145112
Hom.:
0
Cov.:
27
AF XY:
0.000199
AC XY:
14
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.:
0
ExAC
AF:
0.000126
AC:
1

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
T
BayesDel_noAF
Benign
-0.47
CADD
Benign
22
DANN
Uncertain
1.0
DEOGEN2
Benign
0.00063
T
Eigen
Benign
-0.63
Eigen_PC
Benign
-0.53
FATHMM_MKL
Benign
0.18
N
LIST_S2
Benign
0.48
T
MetaRNN
Benign
0.0023
T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.0
N
PrimateAI
Uncertain
0.62
T
PROVEAN
Benign
-0.42
N
REVEL
Benign
0.048
Sift
Benign
0.053
T
Sift4G
Pathogenic
0.0
D
Polyphen
0.030
B
Vest4
0.15
MutPred
0.38
Gain of phosphorylation at A4 (P = 0.0337);
MVP
0.26
MPC
1.5
ClinPred
0.11
T
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.

Other links and lift over

dbSNP: rs771204818; hg19: chr19-44143933; API