chr2-233618215-A-G

Position:

• chr2-233618215-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The ENST00000373450.5(UGT1A8):​c.508A>G​(p.Arg170Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,732 control chromosomes in the GnomAD database, with no homozygous occurrence. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: UGT1A8 ENST00000373450.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.170

Genes affected

UGT1A8 (HGNC:12540): (UDP glucuronosyltransferase family 1 member A8) This gene encodes a UDP-glucuronosyltransferase, an enzyme of the glucuronidation pathway that transforms small lipophilic molecules, such as steroids, bilirubin, hormones, and drugs, into water-soluble, excretable metabolites. This gene is part of a complex locus that encodes several UDP-glucuronosyltransferases. The locus includes thirteen unique alternate first exons followed by four common exons. Four of the alternate first exons are considered pseudogenes. Each of the remaining nine 5' exons may be spliced to the four common exons, resulting in nine proteins with different N-termini and identical C-termini. Each first exon encodes the substrate binding site, and is regulated by its own promoter. The enzyme encoded by this gene has glucuronidase activity with many substrates including coumarins, phenols, anthraquinones, flavones, and some opioids. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UGT1A8	NM_019076.5	c.508A>G	p.Arg170Gly	missense_variant	1/5	ENST00000373450.5	NP_061949.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UGT1A8	ENST00000373450.5	c.508A>G	p.Arg170Gly	missense_variant	1/5	1	NM_019076.5	ENSP00000362549	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461732 Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5 AN XY: 727170

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

May 20, 2024

The c.508A>G (p.R170G) alteration is located in exon 1 (coding exon 1) of the UGT1A8 gene. This alteration results from a A to G substitution at nucleotide position 508, causing the arginine (R) at amino acid position 170 to be replaced by a glycine (G). 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	Pathogenic	0.67
BayesDel_addAF	Benign	-0.028	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	17
DANN	Benign	0.90
DEOGEN2	Uncertain	0.54	D
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.025	T
MetaRNN	Uncertain	0.53	D
MetaSVM	Benign	-0.66	T
MutationAssessor	Pathogenic	3.2	M
MutationTaster	Benign	1.0	N
PROVEAN	Pathogenic	-5.4	D
REVEL	Benign	0.24
Sift	Uncertain	0.020	D
Sift4G	Uncertain	0.024	D
Polyphen		0.023	B
Vest4		0.38
MutPred		0.73		Loss of methylation at R170 (P = 0.0598);
MVP		0.67
ClinPred		0.31	T
GERP RS		2.7
Varity_R		0.28
gMVP		0.44

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-234526861;