19-55401578-T-G

Position:

• chr19-55401578-T-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_014501.3(UBE2S):​c.527A>C​(p.Glu176Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0738 in 1,606,250 control chromosomes in the GnomAD database, including 4,972 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.066 (407 hom., cov: 32)
  • Exomes 𝑓: 0.075 (4565 hom.)
• Consequence: UBE2S NM_014501.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.38

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017818809).
• BP6: Variant 19-55401578-T-G is Benign according to our data. Variant chr19-55401578-T-G is described in ClinVar as [Benign]. Clinvar id is 770812.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0846 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UBE2S	NM_014501.3	c.527A>C	p.Glu176Ala	missense_variant	4/4	ENST00000264552.14
RPL28	NM_001363697.1	c.325-1365T>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UBE2S	ENST00000264552.14	c.527A>C	p.Glu176Ala	missense_variant	4/4	1	NM_014501.3	P1
RPL28	ENST00000560055.5	c.325-1365T>G		intron_variant		3
UBE2S	ENST00000587845.5			downstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.0665 AC: 10120 AN: 152082 Hom.: 407 Cov.: 32

Gnomad AFR AF: 0.0321

Gnomad AMI AF: 0.190

Gnomad AMR AF: 0.0758

Gnomad ASJ AF: 0.143

Gnomad EAS AF: 0.00136

Gnomad SAS AF: 0.0159

Gnomad FIN AF: 0.0738

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.0864

Gnomad OTH AF: 0.0888

GnomAD3 exomes AF: 0.0528 AC: 12341 AN: 233570 Hom.: 441 AF XY: 0.0516 AC XY: 6623 AN XY: 128386

Gnomad AFR exome AF: 0.0257

Gnomad AMR exome AF: 0.0494

Gnomad ASJ exome AF: 0.111

Gnomad EAS exome AF: 0.000458

Gnomad SAS exome AF: 0.0128

Gnomad FIN exome AF: 0.0624

Gnomad NFE exome AF: 0.0698

Gnomad OTH exome AF: 0.0770

GnomAD4 exome AF: 0.0745 AC: 108386 AN: 1454050 Hom.: 4565 Cov.: 30 AF XY: 0.0729 AC XY: 52702 AN XY: 723070

Gnomad4 AFR exome AF: 0.0302

Gnomad4 AMR exome AF: 0.0549

Gnomad4 ASJ exome AF: 0.129

Gnomad4 EAS exome AF: 0.000454

Gnomad4 SAS exome AF: 0.0149

Gnomad4 FIN exome AF: 0.0710

Gnomad4 NFE exome AF: 0.0827

Gnomad4 OTH exome AF: 0.0757

GnomAD4 genome AF: 0.0665 AC: 10119 AN: 152200 Hom.: 407 Cov.: 32 AF XY: 0.0645 AC XY: 4801 AN XY: 74396

Gnomad4 AFR AF: 0.0320

Gnomad4 AMR AF: 0.0757

Gnomad4 ASJ AF: 0.143

Gnomad4 EAS AF: 0.00136

Gnomad4 SAS AF: 0.0162

Gnomad4 FIN AF: 0.0738

Gnomad4 NFE AF: 0.0864

Gnomad4 OTH AF: 0.0879

Alfa AF: 0.0792 Hom.: 159

Bravo AF: 0.0675

TwinsUK AF: 0.0777 AC: 288

ALSPAC AF: 0.0797 AC: 307

ExAC AF: 0.0488 AC: 5800

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.046
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	7.1
DANN	Benign	0.55
DEOGEN2	Benign	0.023	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0083	N
LIST_S2	Benign	0.12	T
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.20	N
MutationTaster	Benign	0.85	D;N
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-0.28	N
REVEL	Benign	0.086
Sift	Benign	0.94	T
Sift4G	Benign	0.73	T
Polyphen		0.0	B
Vest4		0.013
MPC		1.2
ClinPred		0.00054	T
GERP RS		0.76
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
Varity_R		0.031
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: rs61748180; hg19: chr19-55912946; COSMIC: COSV52740410; COSMIC: COSV52740410;