chr2-233713664-C-T

Position:

• chr2-233713664-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000373414.4(UGT1A5):​c.673C>T​(p.His225Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0979 in 1,613,772 control chromosomes in the GnomAD database, including 8,758 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.10 (900 hom., cov: 32)
  • Exomes 𝑓: 0.098 (7858 hom.)
• Consequence: UGT1A5 ENST00000373414.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.17

Genes affected

UGT1A5 (HGNC:12537): (UDP glucuronosyltransferase family 1 member A5) 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. [provided by RefSeq, Jul 2008]

UGT1A6 (HGNC:12538): (UDP glucuronosyltransferase family 1 member A6) 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 is active on phenolic and planar compounds. Alternative splicing in the unique 5' end of this gene results in two transcript variants. [provided by RefSeq, Jul 2008]

UGT1A10 (HGNC:12531): (UDP glucuronosyltransferase family 1 member A10) 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 on mycophenolic acid, coumarins, and quinolines. [provided by RefSeq, Jul 2008]

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]

UGT1A7 (HGNC:12539): (UDP glucuronosyltransferase family 1 member A7) 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 moderate glucuronidase activity with phenols. [provided by RefSeq, Jul 2008]

UGT1A9 (HGNC:12541): (UDP glucuronosyltransferase family 1 member A9) 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 is active on phenols. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017842352).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.194 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UGT1A5	NM_019078.2	c.673C>T	p.His225Tyr	missense_variant	1/5	ENST00000373414.4	NP_061951.1
UGT1A6	NM_001072.4	c.861+19799C>T		intron_variant		ENST00000305139.11	NP_001063.2
UGT1A10	NM_019075.4	c.856-53370C>T		intron_variant		ENST00000344644.10	NP_061948.1
UGT1A8	NM_019076.5	c.856-53370C>T		intron_variant		ENST00000373450.5	NP_061949.3
UGT1A7	NM_019077.3	c.855+30872C>T		intron_variant		ENST00000373426.4	NP_061950.2
UGT1A9	NM_021027.3	c.855+40875C>T		intron_variant		ENST00000354728.5	NP_066307.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UGT1A5	ENST00000373414.4	c.673C>T	p.His225Tyr	missense_variant	1/5	1	NM_019078.2	ENSP00000362513	P1
UGT1A6	ENST00000305139.11	c.861+19799C>T		intron_variant		1	NM_001072.4	ENSP00000303174	P1
UGT1A10	ENST00000344644.10	c.856-53370C>T		intron_variant		1	NM_019075.4	ENSP00000343838	P1
UGT1A9	ENST00000354728.5	c.855+40875C>T		intron_variant		1	NM_021027.3	ENSP00000346768	P1
UGT1A7	ENST00000373426.4	c.855+30872C>T		intron_variant		1	NM_019077.3	ENSP00000362525	P1
UGT1A8	ENST00000373450.5	c.856-53370C>T		intron_variant		1	NM_019076.5	ENSP00000362549	P1

Frequencies

GnomAD3 genomes AF: 0.101 AC: 15412 AN: 152064 Hom.: 896 Cov.: 32

Gnomad AFR AF: 0.104

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.112

Gnomad ASJ AF: 0.102

Gnomad EAS AF: 0.205

Gnomad SAS AF: 0.195

Gnomad FIN AF: 0.0598

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.0902

Gnomad OTH AF: 0.111

GnomAD3 exomes AF: 0.118 AC: 29676 AN: 251120 Hom.: 2111 AF XY: 0.121 AC XY: 16441 AN XY: 135708

Gnomad AFR exome AF: 0.103

Gnomad AMR exome AF: 0.127

Gnomad ASJ exome AF: 0.104

Gnomad EAS exome AF: 0.218

Gnomad SAS exome AF: 0.197

Gnomad FIN exome AF: 0.0661

Gnomad NFE exome AF: 0.0920

Gnomad OTH exome AF: 0.110

GnomAD4 exome AF: 0.0975 AC: 142522 AN: 1461590 Hom.: 7858 Cov.: 34 AF XY: 0.101 AC XY: 73136 AN XY: 727094

Gnomad4 AFR exome AF: 0.103

Gnomad4 AMR exome AF: 0.126

Gnomad4 ASJ exome AF: 0.103

Gnomad4 EAS exome AF: 0.168

Gnomad4 SAS exome AF: 0.195

Gnomad4 FIN exome AF: 0.0720

Gnomad4 NFE exome AF: 0.0866

Gnomad4 OTH exome AF: 0.106

GnomAD4 genome AF: 0.101 AC: 15432 AN: 152182 Hom.: 900 Cov.: 32 AF XY: 0.102 AC XY: 7608 AN XY: 74396

Gnomad4 AFR AF: 0.104

Gnomad4 AMR AF: 0.112

Gnomad4 ASJ AF: 0.102

Gnomad4 EAS AF: 0.204

Gnomad4 SAS AF: 0.194

Gnomad4 FIN AF: 0.0598

Gnomad4 NFE AF: 0.0902

Gnomad4 OTH AF: 0.117

Alfa AF: 0.0960 Hom.: 361

Bravo AF: 0.103

TwinsUK AF: 0.0833 AC: 309

ALSPAC AF: 0.0877 AC: 338

ESP6500AA AF: 0.102 AC: 450

ESP6500EA AF: 0.0862 AC: 741

ExAC AF: 0.120 AC: 14634

Asia WGS AF: 0.199 AC: 690 AN: 3476

EpiCase AF: 0.0945

EpiControl AF: 0.0941

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	0.065
DANN	Benign	0.78
DEOGEN2	Benign	0.093	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0076	N
LIST_S2	Benign	0.15	T
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L
MutationTaster	Benign	1.0	P;P;P;P;P;P;P;P;P
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.028
Sift	Benign	0.20	T
Sift4G	Benign	0.48	T
Polyphen		0.25	B
Vest4		0.036
MPC		0.19
ClinPred		0.025	T
GERP RS		-3.5
Varity_R		0.055
gMVP		0.32

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: rs17862867; hg19: chr2-234622310; COSMIC: COSV59382185; COSMIC: COSV59382185;