3-149333364-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_138786.4(TM4SF18):​c.19G>A​(p.Gly7Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000157 in 1,612,468 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G7E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 31)
Exomes 𝑓: 0.00016 ( 0 hom. )

Consequence

TM4SF18
NM_138786.4 missense

Scores

5
14

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.572
Variant links:
Genes affected
TM4SF18 (HGNC:25181): (transmembrane 4 L six family member 18) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]
TM4SF18-AS1 (HGNC:56678): (TM4SF18 antisense RNA 1)

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.19202822).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TM4SF18NM_138786.4 linkc.19G>A p.Gly7Arg missense_variant Exon 2 of 6 ENST00000296059.7 NP_620141.1 Q96CE8
TM4SF18NM_001184723.2 linkc.19G>A p.Gly7Arg missense_variant Exon 1 of 5 NP_001171652.1 Q96CE8
TM4SF18-AS1NR_186251.1 linkn.405-140C>T intron_variant Intron 1 of 1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TM4SF18ENST00000296059.7 linkc.19G>A p.Gly7Arg missense_variant Exon 2 of 6 1 NM_138786.4 ENSP00000296059.2 Q96CE8

Frequencies

GnomAD3 genomes
AF:
0.000118
AC:
18
AN:
152116
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.000250
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000760
AC:
19
AN:
249984
Hom.:
0
AF XY:
0.0000740
AC XY:
10
AN XY:
135142
show subpopulations
Gnomad AFR exome
AF:
0.0000616
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:
0.000150
Gnomad OTH exome
AF:
0.000165
GnomAD4 exome
AF:
0.000161
AC:
235
AN:
1460352
Hom.:
0
Cov.:
32
AF XY:
0.000147
AC XY:
107
AN XY:
726412
show subpopulations
Gnomad4 AFR exome
AF:
0.00
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:
0.000197
Gnomad4 OTH exome
AF:
0.000265
GnomAD4 genome
AF:
0.000118
AC:
18
AN:
152116
Hom.:
0
Cov.:
31
AF XY:
0.0000673
AC XY:
5
AN XY:
74310
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000250
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000847
Hom.:
0
Bravo
AF:
0.0000718
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000233
AC:
2
ExAC
AF:
0.0000906
AC:
11
EpiCase
AF:
0.000274
EpiControl
AF:
0.000238

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Jan 27, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.19G>A (p.G7R) alteration is located in exon 2 (coding exon 1) of the TM4SF18 gene. This alteration results from a G to A substitution at nucleotide position 19, causing the glycine (G) at amino acid position 7 to be replaced by an arginine (R). 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
0.12
BayesDel_addAF
Benign
-0.28
T
BayesDel_noAF
Benign
-0.34
CADD
Benign
20
DANN
Uncertain
1.0
DEOGEN2
Benign
0.053
T;T;T
Eigen
Benign
-0.022
Eigen_PC
Benign
-0.069
FATHMM_MKL
Benign
0.19
N
LIST_S2
Benign
0.82
.;T;T
M_CAP
Benign
0.011
T
MetaRNN
Benign
0.19
T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Uncertain
2.2
M;M;.
PrimateAI
Uncertain
0.51
T
PROVEAN
Benign
-2.0
N;N;N
REVEL
Benign
0.20
Sift
Uncertain
0.0030
D;D;D
Sift4G
Uncertain
0.0080
D;D;.
Polyphen
0.86
P;P;.
Vest4
0.40
MutPred
0.76
Gain of MoRF binding (P = 0.0109);Gain of MoRF binding (P = 0.0109);Gain of MoRF binding (P = 0.0109);
MVP
0.26
MPC
0.28
ClinPred
0.11
T
GERP RS
2.6
Varity_R
0.18
gMVP
0.69

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.16
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: rs143444839; hg19: chr3-149051151; API