Genetic Variant TMUB1:p.Ser158Asn (chr7-151081817-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

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

The NM_001136044.2(TMUB1):c.473G>A(p.Ser158Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000142 in 1,564,918 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00015 ( 0 hom. )

Consequence

TMUB1
NM_001136044.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.28

Variant links:

Genes affected

TMUB1 (HGNC:21709): (transmembrane and ubiquitin like domain containing 1) Involved in ubiquitin-dependent ERAD pathway. Predicted to be located in several cellular components, including nucleolus; postsynaptic membrane; and recycling endosome. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

TMUB1 links:

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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=0.22444168).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMUB1	NM_001136044.2 link	c.473G>A	p.Ser158Asn	missense_variant	Exon 3 of 3	ENST00000297533.9	NP_001129516.1	Q9BVT8A0A090N8Q3
TMUB1	NM_031434.4 link	c.473G>A	p.Ser158Asn	missense_variant	Exon 3 of 3		NP_113622.1	Q9BVT8A0A090N8Q3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMUB1	ENST00000297533.9 link	c.473G>A	p.Ser158Asn	missense_variant	Exon 3 of 3	1	NM_001136044.2	ENSP00000297533.4		Q9BVT8

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152136

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

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:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000563

AC:

AN:

195534

Hom.:

AF XY:

0.0000665

AC XY:

AN XY:

105318

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000637

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000112

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000150

AC:

212

AN:

1412782

Hom.:

Cov.:

AF XY:

0.000146

AC XY:

102

AN XY:

696718

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000260

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000199

Gnomad4 NFE exome

AF:

0.000177

Gnomad4 OTH exome

AF:

0.000309

GnomAD4 genome

AF:

0.0000657

AC:

AN:

152136

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74312

show subpopulations

Gnomad4 AFR

AF:

0.0000965

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:

0.0000882

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000223

Hom.:

Bravo

AF:

0.0000718

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.0000497

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 08, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.473G>A (p.S158N) alteration is located in exon 3 (coding exon 2) of the TMUB1 gene. This alteration results from a G to A substitution at nucleotide position 473, causing the serine (S) at amino acid position 158 to be replaced by an asparagine (N). 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

0.36

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.41

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.091

T;T;T;T;T;T

Eigen

Benign

-0.13

Eigen_PC

Benign

-0.081

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.73

.;.;.;.;T;T

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.22

T;T;T;T;T;T

MetaSVM

Benign

-0.57

MutationAssessor

Uncertain

2.7

M;M;M;M;M;.

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-2.1

N;N;N;N;N;D

REVEL

Benign

0.24

Sift

Uncertain

0.0010

D;D;D;D;D;D

Sift4G

Uncertain

0.0060

D;D;D;D;D;.

Polyphen

0.024

B;B;B;B;B;.

Vest4

0.29

MVP

0.69

MPC

0.89

ClinPred

0.32

GERP RS

1.3

Varity_R

0.34

gMVP

0.45

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