chr17-16382006-G-T

Variant names:

• chr17-16382006-G-T
• rs397839871
• NM_018955.4:c.99G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM1

The NM_018955.4(UBB):​c.99G>T​(p.Lys33Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. K33K) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: UBB NM_018955.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0270
• 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 2 ACMG points.

• PM1: In a cross_link Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) (size 0) in uniprot entity UBB_HUMAN

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.99G>T	p.Lys33Asn	missense	Exon 2 of 2	NP_061828.1	P0CG47
	UBB	NM_001281716.2		c.99G>T	p.Lys33Asn	missense	Exon 2 of 2	NP_001268645.1	Q5U5U6
	UBB	NM_001281717.1		c.99G>T	p.Lys33Asn	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.99G>T	p.Lys33Asn	missense	Exon 2 of 2	ENSP00000304697.3	P0CG47
	UBB	ENST00000395837.1	TSL:2	c.99G>T	p.Lys33Asn	missense	Exon 2 of 2	ENSP00000379178.1	P0CG47
	UBB	ENST00000395839.5	TSL:2	c.99G>T	p.Lys33Asn	missense	Exon 2 of 2	ENSP00000379180.1	P0CG47

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 129580 Hom.: 0 Cov.: 31

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1437580 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 715298

African (AFR) AF: 0.00 AC: 0 AN: 32360

American (AMR) AF: 0.00 AC: 0 AN: 43322

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25066

East Asian (EAS) AF: 0.00 AC: 0 AN: 38098

South Asian (SAS) AF: 0.00 AC: 0 AN: 85324

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52476

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5638

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1096646

Other (OTH) AF: 0.00 AC: 0 AN: 58650

GnomAD4 genome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 129686 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 63720

African (AFR) AF: 0.00 AC: 0 AN: 34374

American (AMR) AF: 0.00 AC: 0 AN: 13052

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3062

East Asian (EAS) AF: 0.00 AC: 0 AN: 4210

South Asian (SAS) AF: 0.00 AC: 0 AN: 3796

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9044

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 228

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 59366

Other (OTH) AF: 0.00 AC: 0 AN: 1812

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Benign	-0.028	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	16
DANN	Benign	0.63
DEOGEN2	Benign	0.095	T
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.58	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.081	D
MetaRNN	Uncertain	0.72	D
MetaSVM	Uncertain	-0.097	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		-0.027
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-3.9	D
REVEL	Uncertain	0.47
Sift4G	Pathogenic	0.0	D
Polyphen		0.41	B
Vest4		0.63
MutPred		0.55		Loss of ubiquitination at K33 (P = 0.0148)
MVP		0.82
MPC		2.1
ClinPred		0.93	D
GERP RS		-6.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.96
gMVP		0.94

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: rs397839871; hg19: chr17-16285320;