rs6755571

Positions:

• chr2-233718890-C-A
• chr2-233718890-C-T

Variant summary

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

The ENST00000373409.8(UGT1A4):​c.70C>A​(p.Pro24Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0528 in 1,613,968 control chromosomes in the GnomAD database, including 2,693 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 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 0.038 (137 hom., cov: 33)
  • Exomes 𝑓: 0.054 (2556 hom.)
• Consequence: UGT1A4 ENST00000373409.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0790

Genes affected

UGT1A4 (HGNC:12536): (UDP glucuronosyltransferase family 1 member A4) 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. This enzyme has some glucuronidase activity towards bilirubin, although is is more active on amines, steroids, and sapogenins. [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]

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]

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=0.0026385188).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0559 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UGT1A4	NM_007120.3	c.70C>A	p.Pro24Thr	missense_variant	1/5	ENST00000373409.8	NP_009051.1
UGT1A6	NM_001072.4	c.861+25025C>A		intron_variant		ENST00000305139.11	NP_001063.2
UGT1A10	NM_019075.4	c.856-48144C>A		intron_variant		ENST00000344644.10	NP_061948.1
UGT1A8	NM_019076.5	c.856-48144C>A		intron_variant		ENST00000373450.5	NP_061949.3
UGT1A7	NM_019077.3	c.855+36098C>A		intron_variant		ENST00000373426.4	NP_061950.2
UGT1A5	NM_019078.2	c.867+5032C>A		intron_variant		ENST00000373414.4	NP_061951.1
UGT1A9	NM_021027.3	c.855+46101C>A		intron_variant		ENST00000354728.5	NP_066307.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UGT1A4	ENST00000373409.8	c.70C>A	p.Pro24Thr	missense_variant	1/5	1	NM_007120.3	ENSP00000362508	P1
UGT1A6	ENST00000305139.11	c.861+25025C>A		intron_variant		1	NM_001072.4	ENSP00000303174	P1
UGT1A10	ENST00000344644.10	c.856-48144C>A		intron_variant		1	NM_019075.4	ENSP00000343838	P1
UGT1A9	ENST00000354728.5	c.855+46101C>A		intron_variant		1	NM_021027.3	ENSP00000346768	P1
UGT1A5	ENST00000373414.4	c.867+5032C>A		intron_variant		1	NM_019078.2	ENSP00000362513	P1
UGT1A7	ENST00000373426.4	c.855+36098C>A		intron_variant		1	NM_019077.3	ENSP00000362525	P1
UGT1A8	ENST00000373450.5	c.856-48144C>A		intron_variant		1	NM_019076.5	ENSP00000362549	P1

Frequencies

GnomAD3 genomes AF: 0.0379 AC: 5762 AN: 152214 Hom.: 137 Cov.: 33

Gnomad AFR AF: 0.0160

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.0394

Gnomad ASJ AF: 0.0421

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0114

Gnomad FIN AF: 0.0273

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0574

Gnomad OTH AF: 0.0382

GnomAD3 exomes AF: 0.0365 AC: 9168 AN: 251340 Hom.: 264 AF XY: 0.0358 AC XY: 4860 AN XY: 135846

Gnomad AFR exome AF: 0.0158

Gnomad AMR exome AF: 0.0254

Gnomad ASJ exome AF: 0.0388

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0110

Gnomad FIN exome AF: 0.0256

Gnomad NFE exome AF: 0.0572

Gnomad OTH exome AF: 0.0403

GnomAD4 exome AF: 0.0543 AC: 79392 AN: 1461636 Hom.: 2556 Cov.: 32 AF XY: 0.0528 AC XY: 38414 AN XY: 727122

Gnomad4 AFR exome AF: 0.0168

Gnomad4 AMR exome AF: 0.0273

Gnomad4 ASJ exome AF: 0.0390

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.0113

Gnomad4 FIN exome AF: 0.0268

Gnomad4 NFE exome AF: 0.0637

Gnomad4 OTH exome AF: 0.0497

GnomAD4 genome AF: 0.0378 AC: 5756 AN: 152332 Hom.: 137 Cov.: 33 AF XY: 0.0352 AC XY: 2625 AN XY: 74510

Gnomad4 AFR AF: 0.0159

Gnomad4 AMR AF: 0.0393

Gnomad4 ASJ AF: 0.0421

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0112

Gnomad4 FIN AF: 0.0273

Gnomad4 NFE AF: 0.0574

Gnomad4 OTH AF: 0.0374

Alfa AF: 0.0502 Hom.: 125

Bravo AF: 0.0384

TwinsUK AF: 0.0639 AC: 237

ALSPAC AF: 0.0659 AC: 254

ESP6500AA AF: 0.0191 AC: 84

ESP6500EA AF: 0.0543 AC: 467

ExAC AF: 0.0368 AC: 4468

Asia WGS AF: 0.00693 AC: 24 AN: 3476

EpiCase AF: 0.0548

EpiControl AF: 0.0579

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	1.7
DANN	Benign	0.74
DEOGEN2	Benign	0.096	T
Eigen	Benign	-0.99
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.15	T
MetaRNN	Benign	0.0026	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.67	N
REVEL	Benign	0.017
Sift	Benign	0.39	T
Sift4G	Benign	0.40	T
Polyphen		0.053	B
Vest4		0.074
MPC		0.039
ClinPred		0.00062	T
GERP RS		1.3
Varity_R		0.026
gMVP		0.34

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: rs6755571; hg19: chr2-234627536; COSMIC: COSV59394799; COSMIC: COSV59394799;