chr4-69639142-G-A

Variant names:

• chr4-69639142-G-A
• NM_001105677.2:c.499C>T

Variant summary

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

The NM_001105677.2(UGT2A2):​c.499C>T​(p.Leu167Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,504 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: UGT2A2 NM_001105677.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.482

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]

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 rank	MANE	Protein	UniProt
UGT2A2	NM_001105677.2	c.499C>T	p.Leu167Phe	missense_variant	Exon 1 of 6	ENST00000604629.6	NP_001099147.2
UGT2A1	NM_001252275.3	c.716-3320C>T		intron_variant	Intron 2 of 6	ENST00000286604.9	NP_001239204.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UGT2A2	ENST00000604629.6	c.499C>T	p.Leu167Phe	missense_variant	Exon 1 of 6	1	NM_001105677.2	ENSP00000475028.2
UGT2A1	ENST00000286604.9	c.716-3320C>T		intron_variant	Intron 2 of 6	1	NM_001252275.3	ENSP00000286604.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461504 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727016

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00

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

Oct 13, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.499C>T (p.L167F) alteration is located in exon 1 (coding exon 1) of the UGT2A2 gene. This alteration results from a C to T substitution at nucleotide position 499, causing the leucine (L) at amino acid position 167 to be replaced by a phenylalanine (F). 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	Uncertain	0.49
BayesDel_addAF	Uncertain	0.079	D
BayesDel_noAF	Benign	-0.12
CADD	Benign	17
DANN	Uncertain	1.0
Eigen	Benign	-0.034
Eigen_PC	Benign	-0.21
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.73	T;T;T
M_CAP	Benign	0.029	D
MetaRNN	Uncertain	0.53	D;D;D
MetaSVM	Uncertain	-0.23	T
PrimateAI	Benign	0.48	T
PROVEAN	Uncertain	-3.8	D;.;.
REVEL	Uncertain	0.36
Sift	Uncertain	0.0020	D;.;.
Sift4G	Uncertain	0.024	D;D;D
Vest4		0.58
MutPred		0.68		.;Gain of catalytic residue at L167 (P = 0.075);Gain of catalytic residue at L167 (P = 0.075);
MVP		0.34
ClinPred		0.77	D
GERP RS		2.2
gMVP		0.35

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-70504860;