NM_018955.4:c.645A>T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_018955.4(UBB):​c.645A>T​(p.Lys215Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. K215K) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: UBB NM_018955.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0360
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17648003).

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>T	p.Lys215Asn	missense	Exon 2 of 2	NP_061828.1	P0CG47
	UBB	NM_001281716.2		c.645A>T	p.Lys215Asn	missense	Exon 2 of 2	NP_001268645.1	Q5U5U6
	UBB	NM_001281717.1		c.645A>T	p.Lys215Asn	missense	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>T	p.Lys215Asn	missense	Exon 2 of 2	ENSP00000304697.3	P0CG47
	UBB	ENST00000395837.1	TSL:2	c.645A>T	p.Lys215Asn	missense	Exon 2 of 2	ENSP00000379178.1	P0CG47
	UBB	ENST00000395839.5	TSL:2	c.645A>T	p.Lys215Asn	missense	Exon 2 of 2	ENSP00000379180.1	P0CG47

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	22
DANN	Benign	0.82
DEOGEN2	Benign	0.34	T
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.60
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.51	N
PhyloP100		-0.036
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-3.1	D
REVEL	Benign	0.048
Sift4G	Benign	0.27	T
Polyphen		0.0050	B
Vest4		0.38
MutPred		0.46		Loss of methylation at K215 (P = 0.0135)
MVP		0.41
MPC		1.7
ClinPred		0.98	D
GERP RS		1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
gMVP		0.96

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;