Genetic Variant UBC:p.Thr541Thr (chr12-124912149-A-G) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_021009.7(UBC):c.1623T>C(p.Thr541Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00048 ( 0 hom., cov: 3)

Exomes 𝑓: 0.0014 ( 1 hom. )

Failed GnomAD Quality Control

Consequence

UBC
NM_021009.7 synonymous

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -5.30

Publications

0 publications found

Variant links:

Genes affected

UBC (HGNC:12468): (ubiquitin C) This gene represents a ubiquitin gene, ubiquitin C. The encoded protein is a polyubiquitin precursor. Conjugation of ubiquitin monomers or polymers can lead to various effects within a cell, depending on the residues to which ubiquitin is conjugated. Ubiquitination has been associated with protein degradation, DNA repair, cell cycle regulation, kinase modification, endocytosis, and regulation of other cell signaling pathways. [provided by RefSeq, Aug 2010]

UBC links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.74).

BP6

Variant 12-124912149-A-G is Benign according to our data. Variant chr12-124912149-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 2643566.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAdExome4 at 1247 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021009.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UBC	NM_021009.7	MANE Select	c.1623T>C	p.Thr541Thr	synonymous	Exon 2 of 2	NP_066289.3	P0CG48

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
UBC	ENST00000339647.6	TSL:1 MANE Select	c.1623T>C	p.Thr541Thr	synonymous	Exon 2 of 2	ENSP00000344818.5	P0CG48
UBC	ENST00000536769.1	TSL:6	c.1623T>C	p.Thr541Thr	synonymous	Exon 1 of 1	ENSP00000441543.1	P0CG48
UBC	ENST00000874892.1		c.1623T>C	p.Thr541Thr	synonymous	Exon 2 of 2	ENSP00000544951.1

Frequencies

GnomAD3 genomes

AF:

0.000484

AC:

AN:

8266

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.00109

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000923

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000631

AC:

AN:

107822

AF XY:

0.000797

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000511

Gnomad ASJ exome

AF:

0.00435

Gnomad EAS exome

AF:

0.000491

Gnomad FIN exome

AF:

0.000194

Gnomad NFE exome

AF:

0.00105

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00144

AC:

1247

AN:

863320

Hom.:

Cov.:

AF XY:

0.00154

AC XY:

658

AN XY:

427420

show subpopulations

African (AFR)

AF:

0.0000988

AC:

AN:

20238

American (AMR)

AF:

0.000355

AC:

AN:

30998

Ashkenazi Jewish (ASJ)

AF:

0.00674

AC:

AN:

14398

East Asian (EAS)

AF:

0.000332

AC:

AN:

24062

South Asian (SAS)

AF:

0.000291

AC:

AN:

37834

European-Finnish (FIN)

AF:

0.000287

AC:

AN:

34828

Middle Eastern (MID)

AF:

0.00183

AC:

AN:

2182

European-Non Finnish (NFE)

AF:

0.00159

AC:

1057

AN:

665062

Other (OTH)

AF:

0.00139

AC:

AN:

33718

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

107

160

214

267

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

126

168

210

<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

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000476

AC:

AN:

8396

Hom.:

Cov.:

AF XY:

0.000394

AC XY:

AN XY:

5080

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

1814

American (AMR)

AF:

0.00

AC:

AN:

1734

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

East Asian (EAS)

AF:

0.00

AC:

AN:

268

South Asian (SAS)

AF:

0.00

AC:

AN:

246

European-Finnish (FIN)

AF:

0.00109

AC:

AN:

1836

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.000922

AC:

AN:

2170

Other (OTH)

AF:

0.00

AC:

AN:

164

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00376316), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00174

Hom.:

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-5.3

Mutation Taster

=100/0

polymorphism

(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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over