4-69647421-T-C

Variant names:

• chr4-69647421-T-C
• rs1347046
• NM_001252275.3:c.224A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001252275.3(UGT2A1):​c.224A>G​(p.Lys75Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,836 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 5/6 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: UGT2A1 NM_001252275.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.906
• Publications: 25 publications found

Genes affected

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25802463).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001252275.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UGT2A1	NM_001252275.3	MANE Select	c.224A>G	p.Lys75Arg	missense	Exon 2 of 7	NP_001239204.2
	UGT2A1	NM_001389565.1		c.224A>G	p.Lys75Arg	missense	Exon 2 of 8	NP_001376494.1
	UGT2A1	NM_001252274.3		c.224A>G	p.Lys75Arg	missense	Exon 2 of 7	NP_001239203.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UGT2A1	ENST00000286604.9	TSL:1 MANE Select	c.224A>G	p.Lys75Arg	missense	Exon 2 of 7	ENSP00000286604.4
	UGT2A1	ENST00000503640.5	TSL:1	c.224A>G	p.Lys75Arg	missense	Exon 1 of 6	ENSP00000424478.1
	UGT2A1	ENST00000512704.5	TSL:1	c.224A>G	p.Lys75Arg	missense	Exon 1 of 5	ENSP00000421432.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460836 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726658

African (AFR) AF: 0.0000299 AC: 1 AN: 33428

American (AMR) AF: 0.00 AC: 0 AN: 44626

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26044

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39682

South Asian (SAS) AF: 0.00 AC: 0 AN: 86146

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53354

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111468

Other (OTH) AF: 0.00 AC: 0 AN: 60332

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000133 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_noAF	Benign	-0.82
CADD	Benign	18
LIST_S2	Benign	0.10	T
MetaRNN	Benign	0.26	T
PhyloP100		0.91
Sift4G	Uncertain	0.035	D
Vest4		0.049
PromoterAI		-0.019	Neutral
gMVP		0.081

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1347046; hg19: chr4-70513139;