NM_018955.4:c.645A>G

Variant names:

• chr17-16382552-A-G
• rs201547246
• NM_018955.4:c.645A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BP7

The NM_018955.4(UBB):​c.645A>G​(p.Lys215Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0177 in 129,722 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAd4), which may indicate mosaicism or somatic mutations in the reference population data. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00040 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: UBB NM_018955.4 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0360
• Publications: 1 publications found

Genes affected

UBB (HGNC:12463): (ubiquitin B) This gene encodes ubiquitin, one of the most conserved proteins known. Ubiquitin has a major role in targeting cellular proteins for degradation by the 26S proteosome. It is also involved in the maintenance of chromatin structure, the regulation of gene expression, and the stress response. Ubiquitin is synthesized as a precursor protein consisting of either polyubiquitin chains or a single ubiquitin moiety fused to an unrelated protein. This gene consists of three direct repeats of the ubiquitin coding sequence with no spacer sequence. Consequently, the protein is expressed as a polyubiquitin precursor with a final amino acid after the last repeat. An aberrant form of this protein has been detected in patients with Alzheimer's disease and Down syndrome. Pseudogenes of this gene are located on chromosomes 1, 2, 13, and 17. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2013]

UBB Gene-Disease associations (from GenCC):

• isolated cleft palate

  Inheritance: AD Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

ENSG00000265401 (HGNC:58390):

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 17-16382552-A-G is Benign according to our data. Variant chr17-16382552-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 720176.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.036 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018955.4. 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
	UBB	NM_018955.4	MANE Select	c.645A>G	p.Lys215Lys	synonymous	Exon 2 of 2	NP_061828.1	P0CG47
	UBB	NM_001281716.2		c.645A>G	p.Lys215Lys	synonymous	Exon 2 of 2	NP_001268645.1	Q5U5U6
	UBB	NM_001281717.1		c.645A>G	p.Lys215Lys	synonymous	Exon 2 of 2	NP_001268646.1	P0CG47

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UBB	ENST00000302182.8	TSL:1 MANE Select	c.645A>G	p.Lys215Lys	synonymous	Exon 2 of 2	ENSP00000304697.3	P0CG47
	UBB	ENST00000395837.1	TSL:2	c.645A>G	p.Lys215Lys	synonymous	Exon 2 of 2	ENSP00000379178.1	P0CG47
	UBB	ENST00000395839.5	TSL:2	c.645A>G	p.Lys215Lys	synonymous	Exon 2 of 2	ENSP00000379180.1	P0CG47

Frequencies

GnomAD3 genomes AF: 0.0178 AC: 2305 AN: 129636 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0225

Gnomad AMI AF: 0.0427

Gnomad AMR AF: 0.0125

Gnomad ASJ AF: 0.0115

Gnomad EAS AF: 0.0297

Gnomad SAS AF: 0.0180

Gnomad FIN AF: 0.0157

Gnomad MID AF: 0.118

Gnomad NFE AF: 0.0153

Gnomad OTH AF: 0.0187

GnomAD2 exomes AF: 0.00162 AC: 365 AN: 225654 AF XY: 0.00135

Gnomad AFR exome AF: 0.00225

Gnomad AMR exome AF: 0.00380

Gnomad ASJ exome AF: 0.000972

Gnomad EAS exome AF: 0.00288

Gnomad FIN exome AF: 0.0000466

Gnomad NFE exome AF: 0.000872

Gnomad OTH exome AF: 0.00327

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000398 AC: 566 AN: 1421210 Hom.: 0 Cov.: 31 AF XY: 0.000371 AC XY: 262 AN XY: 707030

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

African (AFR) AF: 0.00113 AC: 35 AN: 30840

American (AMR) AF: 0.00442 AC: 171 AN: 38718

Ashkenazi Jewish (ASJ) AF: 0.000325 AC: 8 AN: 24642

East Asian (EAS) AF: 0.00189 AC: 67 AN: 35410

South Asian (SAS) AF: 0.000919 AC: 76 AN: 82712

European-Finnish (FIN) AF: 0.0000189 AC: 1 AN: 52802

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5546

European-Non Finnish (NFE) AF: 0.000161 AC: 176 AN: 1092446

Other (OTH) AF: 0.000551 AC: 32 AN: 58094

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0177 AC: 2297 AN: 129722 Hom.: 0 Cov.: 32 AF XY: 0.0160 AC XY: 1023 AN XY: 64024

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

African (AFR) AF: 0.0224 AC: 779 AN: 34714

American (AMR) AF: 0.0125 AC: 168 AN: 13470

Ashkenazi Jewish (ASJ) AF: 0.0115 AC: 35 AN: 3052

East Asian (EAS) AF: 0.0298 AC: 125 AN: 4198

South Asian (SAS) AF: 0.0181 AC: 72 AN: 3986

European-Finnish (FIN) AF: 0.0157 AC: 143 AN: 9128

Middle Eastern (MID) AF: 0.102 AC: 20 AN: 196

European-Non Finnish (NFE) AF: 0.0153 AC: 893 AN: 58500

Other (OTH) AF: 0.0180 AC: 32 AN: 1776

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0464 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	11
DANN	Benign	0.70
PhyloP100		-0.036
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs201547246; hg19: chr17-16285866; COSMIC: COSV56218789; COSMIC: COSV56218789;