3-149377388-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_014220.3(TM4SF1):​c.160G>A​(p.Val54Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000304 in 1,613,744 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000032 ( 0 hom. )

Consequence

TM4SF1
NM_014220.3 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.482
Variant links:
Genes affected
TM4SF1 (HGNC:11853): (transmembrane 4 L six family member 1) The protein encoded by this gene is a member of the transmembrane 4 superfamily, also known as the tetraspanin family. Most of these members are cell-surface proteins that are characterized by the presence of four hydrophobic domains. The proteins mediate signal transduction events that play a role in the regulation of cell development, activation, growth and motility. This encoded protein is a cell surface antigen and is highly expressed in different carcinomas. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.06622869).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TM4SF1NM_014220.3 linkc.160G>A p.Val54Ile missense_variant Exon 1 of 5 ENST00000305366.8 NP_055035.1 P30408
TM4SF1NM_001410837.1 linkc.160G>A p.Val54Ile missense_variant Exon 1 of 3 NP_001397766.1
TM4SF1XM_017006385.3 linkc.160G>A p.Val54Ile missense_variant Exon 1 of 5 XP_016861874.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TM4SF1ENST00000305366.8 linkc.160G>A p.Val54Ile missense_variant Exon 1 of 5 1 NM_014220.3 ENSP00000304277.3 P30408
TM4SF1ENST00000493298.1 linkn.160G>A non_coding_transcript_exon_variant Exon 1 of 3 4 ENSP00000418025.1 F8WBG6
TM4SF1ENST00000493348.1 linkn.160G>A non_coding_transcript_exon_variant Exon 1 of 4 2 ENSP00000419426.1 F8WF27

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152218
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
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:
0.0000147
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.00000797
AC:
2
AN:
250998
Hom.:
0
AF XY:
0.0000147
AC XY:
2
AN XY:
135630
show subpopulations
Gnomad AFR exome
AF:
0.00
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:
0.0000176
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000322
AC:
47
AN:
1461526
Hom.:
0
Cov.:
30
AF XY:
0.0000358
AC XY:
26
AN XY:
727042
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000348
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000369
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152218
Hom.:
0
Cov.:
33
AF XY:
0.0000269
AC XY:
2
AN XY:
74364
show subpopulations
Gnomad4 AFR
AF:
0.00
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:
0.0000147
Gnomad4 OTH
AF:
0.000478
Alfa
AF:
0.0000675
Hom.:
0
Bravo
AF:
0.00000756
ExAC
AF:
0.0000247
AC:
3
Asia WGS
AF:
0.000866
AC:
3
AN:
3478
EpiCase
AF:
0.000109
EpiControl
AF:
0.00

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Oct 07, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.160G>A (p.V54I) alteration is located in exon 1 (coding exon 1) of the TM4SF1 gene. This alteration results from a G to A substitution at nucleotide position 160, causing the valine (V) at amino acid position 54 to be replaced by an isoleucine (I). 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
0.074
BayesDel_addAF
Benign
-0.36
T
BayesDel_noAF
Benign
-0.73
CADD
Benign
8.9
DANN
Benign
0.87
DEOGEN2
Benign
0.013
T
Eigen
Benign
-1.4
Eigen_PC
Benign
-1.4
FATHMM_MKL
Benign
0.17
N
LIST_S2
Benign
0.59
T
M_CAP
Benign
0.0078
T
MetaRNN
Benign
0.066
T
MetaSVM
Benign
-0.97
T
MutationAssessor
Benign
0.060
N
PrimateAI
Benign
0.23
T
PROVEAN
Benign
0.46
N
REVEL
Benign
0.012
Sift
Benign
0.41
T
Sift4G
Benign
1.0
T
Polyphen
0.0020
B
Vest4
0.045
MutPred
0.46
Loss of glycosylation at S51 (P = 0.066);
MVP
0.030
MPC
0.041
ClinPred
0.019
T
GERP RS
-2.4
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.021
gMVP
0.24

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: rs764592169; hg19: chr3-149095175; API