12-124912641-G-A

Variant names:

• chr12-124912641-G-A
• rs755107448
• NM_021009.7:c.1131C>T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_021009.7(UBC):​c.1131C>T​(p.Leu377Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000925 in 133,036 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 Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00092 (0 hom., cov: 24)
  • Exomes 𝑓: 0.000014 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: UBC NM_021009.7 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.98

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]

ACMG classification

Verdict is Benign. Variant got -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 12-124912641-G-A is Benign according to our data. Variant chr12-124912641-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3465045.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-1.98 with no splicing effect.
• BS2: High AC in GnomAd4 at 123 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UBC	NM_021009.7	c.1131C>T	p.Leu377Leu	synonymous_variant	Exon 2 of 2	ENST00000339647.6	NP_066289.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UBC	ENST00000339647.6	c.1131C>T	p.Leu377Leu	synonymous_variant	Exon 2 of 2	1	NM_021009.7	ENSP00000344818.5
UBC	ENST00000536769.1	c.1131C>T	p.Leu377Leu	synonymous_variant	Exon 1 of 1	6		ENSP00000441543.1
UBC	ENST00000538617.5	c.452-461C>T		intron_variant	Intron 3 of 3	5		ENSP00000443053.1

Frequencies

GnomAD3 genomes AF: 0.000918 AC: 122 AN: 132958 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.00145

Gnomad AMI AF: 0.00130

Gnomad AMR AF: 0.000598

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000677

Gnomad SAS AF: 0.00100

Gnomad FIN AF: 0.00183

Gnomad MID AF: 0.00870

Gnomad NFE AF: 0.000571

Gnomad OTH AF: 0.00109

GnomAD3 exomes AF: 0.0000161 AC: 4 AN: 248916 Hom.: 0 AF XY: 0.0000149 AC XY: 2 AN XY: 134586

Gnomad AFR exome AF: 0.000124

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000332

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000885

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000137 AC: 20 AN: 1459588 Hom.: 0 Cov.: 38 AF XY: 0.0000110 AC XY: 8 AN XY: 726126

Gnomad4 AFR exome AF: 0.0000600

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000117

Gnomad4 OTH exome AF: 0.0000664

GnomAD4 genome AF: 0.000925 AC: 123 AN: 133036 Hom.: 0 Cov.: 24 AF XY: 0.00101 AC XY: 66 AN XY: 65050

Gnomad4 AFR AF: 0.00145

Gnomad4 AMR AF: 0.000598

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000905

Gnomad4 SAS AF: 0.00101

Gnomad4 FIN AF: 0.00183

Gnomad4 NFE AF: 0.000571

Gnomad4 OTH AF: 0.00108

Alfa AF: 0.00174 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Nov 11, 2024

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	1.9
DANN	Benign	0.92

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

Other links and lift over

dbSNP: rs755107448; hg19: chr12-125397187; COSMIC: COSV60059679; COSMIC: COSV60059679;