rs4148301

Positions:

• chr4-69596324-C-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 1P and 12B. PP3 BP4_Strong BA1

The NM_001105677.2(UGT2A2):​c.949G>A​(p.Gly317Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0847 in 1,606,364 control chromosomes in the GnomAD database, including 6,205 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.082 (578 hom., cov: 32)
  • Exomes 𝑓: 0.085 (5627 hom.)
• Consequence: UGT2A2 NM_001105677.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.61

Genes affected

UGT2A2 (HGNC:28183): (UDP glucuronosyltransferase family 2 member A2) The protein encoded by this gene belongs to the UDP-glycosyltransferase family. Members of this protein family play a role in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. The encoded enzyme is expressed in the olfactory neuroepithelium, which lines the posterior nasal cavity and is exposed to a wide range of odorants and airborne toxic compounds. Hence, this protein has been suggested to be involved in clearing lipophilic odorant molecules from the sensory epithelium. This gene shares exon structure with the UDP glucuronosyltransferase 2A1 family member, which encodes N-terminally distinct isoforms. Polymorphisms in this gene may be associated with the loss of taste and smell that is reported by some individuals during SARS-CoV-2 infection. [provided by RefSeq, Jan 2022]

UGT2A1 (HGNC:12542): (UDP glucuronosyltransferase family 2 member A1 complex locus) The protein encoded by this gene belongs to the UDP-glycosyltransferase family. Members of this protein family play a role in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. The encoded enzyme is expressed in the olfactory neuroepithelium, which lines the posterior nasal cavity and is exposed to a wide range of odorants and airborne toxic compounds. Hence, this protein has been suggested to be involved in clearing lipophilic odorant molecules from the sensory epithelium. This gene shares exon structure with the UDP glucuronosyltransferase 2A2 family member, which encodes N-terminally distinct isoforms. Polymorphisms in this gene may be associated with the loss of taste and smell that is reported by some individuals during SARS-CoV-2 infection. [provided by RefSeq, Jan 2022]

UGT2A1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -11 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 8: AlphaMissense, BayesDel_noAF, Cadd, Dann, Eigen, phyloP100way_vertebrate, PROVEAN, REVEL [when BayesDel_addAF, max_spliceai, FATHMM_MKL, MetaRNN was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.0051986873).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0884 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UGT2A2	NM_001105677.2	c.949G>A	p.Gly317Arg	missense_variant	3/6	ENST00000604629.6	NP_001099147.2
UGT2A1	NM_001252275.3	c.997-1075G>A		intron_variant		ENST00000286604.9	NP_001239204.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UGT2A2	ENST00000604629.6	c.949G>A	p.Gly317Arg	missense_variant	3/6	1	NM_001105677.2	ENSP00000475028.2
UGT2A1	ENST00000286604.9	c.997-1075G>A		intron_variant		1	NM_001252275.3	ENSP00000286604.4

Frequencies

GnomAD3 genomes AF: 0.0819 AC: 12439 AN: 151930 Hom.: 578 Cov.: 32

Gnomad AFR AF: 0.0633

Gnomad AMI AF: 0.0330

Gnomad AMR AF: 0.0794

Gnomad ASJ AF: 0.145

Gnomad EAS AF: 0.0518

Gnomad SAS AF: 0.0636

Gnomad FIN AF: 0.102

Gnomad MID AF: 0.177

Gnomad NFE AF: 0.0903

Gnomad OTH AF: 0.109

GnomAD3 exomes AF: 0.0798 AC: 19772 AN: 247870 Hom.: 913 AF XY: 0.0815 AC XY: 10936 AN XY: 134102

Gnomad AFR exome AF: 0.0635

Gnomad AMR exome AF: 0.0497

Gnomad ASJ exome AF: 0.150

Gnomad EAS exome AF: 0.0487

Gnomad SAS exome AF: 0.0638

Gnomad FIN exome AF: 0.0954

Gnomad NFE exome AF: 0.0901

Gnomad OTH exome AF: 0.0992

GnomAD4 exome AF: 0.0850 AC: 123636 AN: 1454314 Hom.: 5627 Cov.: 31 AF XY: 0.0849 AC XY: 61441 AN XY: 723494

Gnomad4 AFR exome AF: 0.0640

Gnomad4 AMR exome AF: 0.0558

Gnomad4 ASJ exome AF: 0.151

Gnomad4 EAS exome AF: 0.0497

Gnomad4 SAS exome AF: 0.0650

Gnomad4 FIN exome AF: 0.0940

Gnomad4 NFE exome AF: 0.0870

Gnomad4 OTH exome AF: 0.0923

GnomAD4 genome AF: 0.0818 AC: 12441 AN: 152050 Hom.: 578 Cov.: 32 AF XY: 0.0823 AC XY: 6113 AN XY: 74314

Gnomad4 AFR AF: 0.0633

Gnomad4 AMR AF: 0.0794

Gnomad4 ASJ AF: 0.145

Gnomad4 EAS AF: 0.0515

Gnomad4 SAS AF: 0.0633

Gnomad4 FIN AF: 0.102

Gnomad4 NFE AF: 0.0902

Gnomad4 OTH AF: 0.111

Alfa AF: 0.0910 Hom.: 1447

Bravo AF: 0.0808

TwinsUK AF: 0.0860 AC: 319

ALSPAC AF: 0.0848 AC: 327

ESP6500AA AF: 0.0763 AC: 336

ESP6500EA AF: 0.0998 AC: 858

ExAC AF: 0.0816 AC: 9903

Asia WGS AF: 0.0610 AC: 212 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Benign	-0.098	T
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	29
DANN	Pathogenic	1.0
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	.;D
MetaRNN	Benign	0.0052	T;T
MetaSVM	Benign	-0.39	T
PROVEAN	Pathogenic	-7.4	D;.
REVEL	Pathogenic	0.82
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0010	D;D
Vest4		0.96
MutPred		0.35		Gain of MoRF binding (P = 0.0088);.;
MPC		0.068
ClinPred		0.12	T
GERP RS		5.4
gMVP		0.76

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs4148301; hg19: chr4-70462042; COSMIC: COSV54138928;