Variant chr3-149475043-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_004617.4(TM4SF4):c.166G>A(p.Gly56Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000106 in 1,603,534 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000035 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

TM4SF4
NM_004617.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.29

Variant links:

Genes affected

TM4SF4 (HGNC:11856): (transmembrane 4 L six family member 4) 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 glycoprotein that can regulate cell proliferation.[provided by RefSeq, Mar 2011]

TM4SF4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.885

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TM4SF4	NM_004617.4 linkuse as main transcript	c.166G>A	p.Gly56Ser	missense_variant	1/5	ENST00000305354.5	NP_004608.1	P48230

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TM4SF4	ENST00000305354.5 linkuse as main transcript	c.166G>A	p.Gly56Ser	missense_variant	1/5	1	NM_004617.4	ENSP00000305852.4		P48230
TM4SF4	ENST00000465758.1 linkuse as main transcript	c.166G>A	p.Gly56Ser	missense_variant	1/2	3		ENSP00000419367.1		C9JVD2

Frequencies

GnomAD3 genomes

AF:

0.0000350

AC:

AN:

142996

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000498

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000741

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000221

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000157

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000572

AC:

AN:

244726

Hom.:

AF XY:

0.0000451

AC XY:

AN XY:

133062

show subpopulations

Gnomad AFR exome

AF:

0.0000650

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000558

Gnomad SAS exome

AF:

0.0000331

Gnomad FIN exome

AF:

0.0000492

Gnomad NFE exome

AF:

0.00000897

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000822

AC:

AN:

1460538

Hom.:

Cov.:

AF XY:

0.00000826

AC XY:

AN XY:

726600

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000190

Gnomad4 NFE exome

AF:

0.00000630

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000350

AC:

AN:

142996

Hom.:

Cov.:

AF XY:

0.0000287

AC XY:

AN XY:

69658

show subpopulations

Gnomad4 AFR

AF:

0.0000498

Gnomad4 AMR

AF:

0.0000741

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000221

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000157

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.0000378

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.0000745

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 11, 2024

The c.166G>A (p.G56S) alteration is located in exon 1 (coding exon 1) of the TM4SF4 gene. This alteration results from a G to A substitution at nucleotide position 166, causing the glycine (G) at amino acid position 56 to be replaced by a serine (S). 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

Uncertain

0.48

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Pathogenic

0.26

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.35

T;.

Eigen

Pathogenic

0.73

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.93

D;D

M_CAP

Uncertain

0.14

MetaRNN

Pathogenic

0.88

D;D

MetaSVM

Uncertain

0.30

MutationAssessor

Pathogenic

3.8

H;.

PrimateAI

Uncertain

0.59

PROVEAN

Pathogenic

-5.4

D;D

REVEL

Pathogenic

0.74

Sift

Uncertain

0.0040

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;.

Vest4

0.70

MutPred

0.81

Loss of glycosylation at S55 (P = 0.0197);Loss of glycosylation at S55 (P = 0.0197);

MVP

0.83

MPC

0.23

ClinPred

0.69

GERP RS

4.2

Varity_R

0.71

gMVP

0.95

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