Genetic Variant TMUB2:n.*1273T>C (chr17-44191649-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The ENST00000587326.1(TMUB2):n.*1273T>C variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.339 in 985,546 control chromosomes in the GnomAD database, including 66,481 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.49 ( 22633 hom., cov: 32)

Exomes 𝑓: 0.31 ( 43848 hom. )

Consequence

TMUB2
ENST00000587326.1 non_coding_transcript_exon

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0570

Publications

18 publications found

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:

ATXN7L3 (HGNC:25416): (ataxin 7 like 3) Enables nuclear receptor coactivator activity. Involved in histone deubiquitination; histone monoubiquitination; and positive regulation of transcription, DNA-templated. Located in nucleus. Part of DUBm complex and SAGA complex. [provided by Alliance of Genome Resources, Apr 2022]

ATXN7L3 Gene-Disease associations (from GenCC):

complex neurodevelopmental disorder
Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics

ATXN7L3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.91).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.839 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMUB2	NM_001076674.3 link	c.*785T>C		3_prime_UTR_variant	Exon 4 of 4	ENST00000538716.7	NP_001070142.1	Q71RG4-1
ATXN7L3	NM_001382309.1 link	c.*2614A>G		downstream_gene_variant		ENST00000587097.6	NP_001369238.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMUB2	ENST00000538716.7 link	c.*785T>C		3_prime_UTR_variant	Exon 4 of 4	2	NM_001076674.3	ENSP00000444565.1		Q71RG4-1
ATXN7L3	ENST00000587097.6 link	c.*2614A>G		downstream_gene_variant		5	NM_001382309.1	ENSP00000465614.2		Q14CW9-1K7EKG9

Frequencies

GnomAD3 genomes

AF:

0.490

AC:

74446

AN:

151900

Hom.:

22568

Cov.:

show subpopulations

Gnomad AFR

AF:

0.846

Gnomad AMI

AF:

0.290

Gnomad AMR

AF:

0.454

Gnomad ASJ

AF:

0.488

Gnomad EAS

AF:

0.773

Gnomad SAS

AF:

0.313

Gnomad FIN

AF:

0.314

Gnomad MID

AF:

0.348

Gnomad NFE

AF:

0.305

Gnomad OTH

AF:

0.446

GnomAD4 exome

AF:

0.311

AC:

259562

AN:

833528

Hom.:

43848

Cov.:

AF XY:

0.310

AC XY:

119336

AN XY:

384978

show subpopulations

African (AFR)

AF:

0.888

AC:

14009

AN:

15784

American (AMR)

AF:

0.438

AC:

431

AN:

984

Ashkenazi Jewish (ASJ)

AF:

0.487

AC:

2509

AN:

5152

East Asian (EAS)

AF:

0.774

AC:

2810

AN:

3632

South Asian (SAS)

AF:

0.299

AC:

4926

AN:

16460

European-Finnish (FIN)

AF:

0.320

AC:

218

AN:

682

Middle Eastern (MID)

AF:

0.358

AC:

580

AN:

1620

European-Non Finnish (NFE)

AF:

0.294

AC:

223913

AN:

761912

Other (OTH)

AF:

0.372

AC:

10166

AN:

27302

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

9960

19920

29881

39841

49801

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10362

20724

31086

41448

51810

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.491

AC:

74576

AN:

152018

Hom.:

22633

Cov.:

AF XY:

0.489

AC XY:

36298

AN XY:

74298

show subpopulations

African (AFR)

AF:

0.846

AC:

35101

AN:

41488

American (AMR)

AF:

0.455

AC:

6946

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.488

AC:

1690

AN:

3464

East Asian (EAS)

AF:

0.773

AC:

3985

AN:

5154

South Asian (SAS)

AF:

0.312

AC:

1503

AN:

4818

European-Finnish (FIN)

AF:

0.314

AC:

3324

AN:

10574

Middle Eastern (MID)

AF:

0.340

AC:

100

AN:

294

European-Non Finnish (NFE)

AF:

0.305

AC:

20725

AN:

67938

Other (OTH)

AF:

0.445

AC:

939

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1521

3042

4563

6084

7605

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

598

1196

1794

2392

2990

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.393

Hom.:

3397

Bravo

AF:

0.524

Asia WGS

AF:

0.537

AC:

1871

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

4.0

(source)

DANN

Benign

0.60

PhyloP100

0.057

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over