chr19-55401603-C-T

Position:

• chr19-55401603-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_014501.3(UBE2S):​c.502G>A​(p.Gly168Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000151 in 1,606,398 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: UBE2S NM_014501.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.471

Genes affected

UBE2S (HGNC:17895): (ubiquitin conjugating enzyme E2 S) This gene encodes a member of the ubiquitin-conjugating enzyme family. The encoded protein is able to form a thiol ester linkage with ubiquitin in a ubiquitin activating enzyme-dependent manner, a characteristic property of ubiquitin carrier proteins. [provided by RefSeq, Jul 2008]

RPL28 (HGNC:10330): (ribosomal protein L28) Ribosomes, the organelles that catalyze protein synthesis, consist of a small 40S subunit and a large 60S subunit. Together these subunits are composed of 4 RNA species and approximately 80 structurally distinct proteins. This gene encodes a ribosomal protein that is a component of the 60S subunit. The protein belongs to the L28E family of ribosomal proteins. It is located in the cytoplasm. Variable expression of this gene in colorectal cancers compared to adjacent normal tissues has been observed, although no correlation between the level of expression and the severity of the disease has been found. As is typical for genes encoding ribosomal proteins, there are multiple processed pseudogenes of this gene dispersed through the genome. Alternative splicing results in multiple transcript variants encoding distinct isoforms.[provided by RefSeq, Oct 2008]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007177919).
• BS2: High AC in GnomAd4 at 23 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UBE2S	NM_014501.3	c.502G>A	p.Gly168Ser	missense_variant	4/4	ENST00000264552.14	NP_055316.2
RPL28	NM_001363697.1	c.325-1340C>T		intron_variant			NP_001350626.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UBE2S	ENST00000264552.14	c.502G>A	p.Gly168Ser	missense_variant	4/4	1	NM_014501.3	ENSP00000264552	P1
UBE2S	ENST00000587845.5	c.589G>A	p.Gly197Ser	missense_variant	5/5	2		ENSP00000467409
RPL28	ENST00000560055.5	c.325-1340C>T		intron_variant		3		ENSP00000452763

Frequencies

GnomAD3 genomes AF: 0.000151 AC: 23 AN: 152216 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000210 AC: 48 AN: 229098 Hom.: 0 AF XY: 0.000229 AC XY: 29 AN XY: 126828

Gnomad AFR exome AF: 0.000154

Gnomad AMR exome AF: 0.000150

Gnomad ASJ exome AF: 0.00297

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000997

Gnomad FIN exome AF: 0.0000486

Gnomad NFE exome AF: 0.0000699

Gnomad OTH exome AF: 0.000358

GnomAD4 exome AF: 0.000151 AC: 219 AN: 1454182 Hom.: 0 Cov.: 30 AF XY: 0.000153 AC XY: 111 AN XY: 723154

Gnomad4 AFR exome AF: 0.0000900

Gnomad4 AMR exome AF: 0.000137

Gnomad4 ASJ exome AF: 0.00347

Gnomad4 EAS exome AF: 0.0000758

Gnomad4 SAS exome AF: 0.0000815

Gnomad4 FIN exome AF: 0.0000194

Gnomad4 NFE exome AF: 0.0000919

Gnomad4 OTH exome AF: 0.000117

GnomAD4 genome AF: 0.000151 AC: 23 AN: 152216 Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8 AN XY: 74360

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00432

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000361 Hom.: 0

Bravo AF: 0.000178

ExAC AF: 0.000171 AC: 20

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 25, 2022

The c.502G>A (p.G168S) alteration is located in exon 4 (coding exon 4) of the UBE2S gene. This alteration results from a G to A substitution at nucleotide position 502, causing the glycine (G) at amino acid position 168 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	0.061
DANN	Benign	0.69
DEOGEN2	Benign	0.024	T;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.079	N
LIST_S2	Benign	0.57	T;T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.0072	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	0.090	N;.
REVEL	Benign	0.045
Sift	Benign	0.44	T;.
Sift4G	Benign	0.70	T;.
Polyphen		0.0	B;.
Vest4		0.040
MutPred		0.22		Gain of glycosylation at G168 (P = 0.0078);.;
MVP		0.33
MPC		1.1
ClinPred		0.0030	T
GERP RS		-8.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
Varity_R		0.036
gMVP		0.30

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: rs753918789; hg19: chr19-55912971;