Genetic Variant NM_001076674.3:c.277A>C (chr17-44189263-A-C) – 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_001076674.3(TMUB2):c.277A>C(p.Asn93His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000721 in 1,607,918 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000076 ( 0 hom. )

Consequence

TMUB2
NM_001076674.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.505

Variant links:

Genes affected

TMUB2 (HGNC:28459): (transmembrane and ubiquitin like domain containing 2) Predicted to be involved in ubiquitin-dependent ERAD pathway. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

TMUB2 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=0.07429859).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMUB2	NM_001076674.3 link	c.277A>C	p.Asn93His	missense_variant	Exon 3 of 4	ENST00000538716.7	NP_001070142.1	Q71RG4-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMUB2	ENST00000538716.7 link	c.277A>C	p.Asn93His	missense_variant	Exon 3 of 4	2	NM_001076674.3	ENSP00000444565.1		Q71RG4-1

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152154

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:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000408

AC:

AN:

245142

Hom.:

AF XY:

0.0000302

AC XY:

AN XY:

132252

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:

0.0000905

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000762

AC:

111

AN:

1455764

Hom.:

Cov.:

AF XY:

0.0000732

AC XY:

AN XY:

723698

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000225

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:

0.0000902

Gnomad4 OTH exome

AF:

0.000150

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152154

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74318

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:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000874

Hom.:

Bravo

AF:

0.0000491

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000577

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 20, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.277A>C (p.N93H) alteration is located in exon 3 (coding exon 2) of the TMUB2 gene. This alteration results from a A to C substitution at nucleotide position 277, causing the asparagine (N) at amino acid position 93 to be replaced by a histidine (H). 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

0.072

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.71

CADD

Benign

DANN

Uncertain

0.97

DEOGEN2

Benign

0.013

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

Eigen

Benign

-0.75

Eigen_PC

Benign

-0.69

FATHMM_MKL

Benign

0.33

LIST_S2

Benign

0.76

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

M_CAP

Benign

0.0065

MetaRNN

Benign

0.074

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

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

.;.;N;N;.;.;.;.;.;.

PrimateAI

Benign

0.39

PROVEAN

Benign

-1.7

N;N;N;.;.;N;.;.;.;.

REVEL

Benign

0.028

Sift

Benign

0.076

T;D;D;.;.;D;.;.;.;.

Sift4G

Benign

0.064

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

Polyphen

0.12

B;.;B;B;B;.;.;B;B;B

Vest4

0.15

MVP

0.46

MPC

0.092

ClinPred

0.029

GERP RS

0.46

Varity_R

0.061

gMVP

0.26

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