Genetic Variant TMUB1:p.Ala27Ser (chr7-151082485-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001136044.2(TMUB1):c.79G>T(p.Ala27Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000442 in 1,583,626 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. A27V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

TMUB1
NM_001136044.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.58

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 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMUB1	NM_001136044.2 link	c.79G>T	p.Ala27Ser	missense_variant	Exon 2 of 3	ENST00000297533.9	NP_001129516.1	Q9BVT8A0A090N8Q3
TMUB1	NM_031434.4 link	c.79G>T	p.Ala27Ser	missense_variant	Exon 2 of 3		NP_113622.1	Q9BVT8A0A090N8Q3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMUB1	ENST00000297533.9 link	c.79G>T	p.Ala27Ser	missense_variant	Exon 2 of 3	1	NM_001136044.2	ENSP00000297533.4		Q9BVT8

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152132

Hom.:

Cov.:

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000445

AC:

AN:

224506

Hom.:

AF XY:

0.00000820

AC XY:

AN XY:

122010

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:

0.00000978

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000279

AC:

AN:

1431494

Hom.:

Cov.:

AF XY:

0.00000563

AC XY:

AN XY:

710396

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:

0.00000365

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152132

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74322

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:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 30, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.79G>T (p.A27S) alteration is located in exon 2 (coding exon 1) of the TMUB1 gene. This alteration results from a G to T substitution at nucleotide position 79, causing the alanine (A) at amino acid position 27 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

Benign

0.30

BayesDel_addAF

Benign

-0.056

BayesDel_noAF

Benign

-0.29

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.29

T;T;T;T;T;T;.

Eigen

Uncertain

0.65

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.83

.;.;.;.;T;T;T

M_CAP

Uncertain

0.15

MetaRNN

Uncertain

0.48

T;T;T;T;T;T;T

MetaSVM

Benign

-0.51

MutationAssessor

Uncertain

2.4

M;M;M;M;M;.;.

PrimateAI

Uncertain

0.64

PROVEAN

Uncertain

-2.6

D;D;D;D;D;N;D

REVEL

Benign

0.24

Sift

Pathogenic

0.0

D;D;D;D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;D;.;D

Polyphen

1.0

D;D;D;D;D;.;.

Vest4

0.54

MVP

0.64

MPC

0.87

ClinPred

0.98

GERP RS

4.8

Varity_R

0.61

gMVP

0.67

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