rs4148254

Variant names:

• chr4-114623557-C-T
• rs4148254
• NM_001128174.3:c.677C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001128174.3(UGT8):​c.677C>T​(p.Pro226Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0344 in 1,613,928 control chromosomes in the GnomAD database, including 1,562 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 0.031 (133 hom., cov: 32)
  • Exomes 𝑓: 0.035 (1429 hom.)
• Consequence: UGT8 NM_001128174.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.81
• Publications: 26 publications found

Genes affected

UGT8 (HGNC:12555): (UDP glycosyltransferase 8) The protein encoded by this gene belongs to the UDP-glycosyltransferase family. It catalyzes the transfer of galactose to ceramide, a key enzymatic step in the biosynthesis of galactocerebrosides, which are abundant sphingolipids of the myelin membrane of the central and peripheral nervous systems. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Sep 2011]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0025598109).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.131 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UGT8	NM_001128174.3	c.677C>T	p.Pro226Leu	missense_variant	Exon 2 of 6	ENST00000310836.11	NP_001121646.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UGT8	ENST00000310836.11	c.677C>T	p.Pro226Leu	missense_variant	Exon 2 of 6	1	NM_001128174.3	ENSP00000311648.6
UGT8	ENST00000394511.3	c.677C>T	p.Pro226Leu	missense_variant	Exon 1 of 5	1		ENSP00000378019.3
UGT8	ENST00000507710.2	c.677C>T	p.Pro226Leu	missense_variant	Exon 3 of 7	3		ENSP00000421446.2

Frequencies

GnomAD3 genomes AF: 0.0309 AC: 4690 AN: 151970 Hom.: 133 Cov.: 32

Gnomad AFR AF: 0.00674

Gnomad AMI AF: 0.0275

Gnomad AMR AF: 0.0528

Gnomad ASJ AF: 0.0724

Gnomad EAS AF: 0.140

Gnomad SAS AF: 0.0565

Gnomad FIN AF: 0.0101

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0317

Gnomad OTH AF: 0.0301

GnomAD2 exomes AF: 0.0473 AC: 11895 AN: 251426 AF XY: 0.0461

Gnomad AFR exome AF: 0.00480

Gnomad AMR exome AF: 0.0850

Gnomad ASJ exome AF: 0.0660

Gnomad EAS exome AF: 0.141

Gnomad FIN exome AF: 0.0114

Gnomad NFE exome AF: 0.0318

Gnomad OTH exome AF: 0.0384

GnomAD4 exome AF: 0.0348 AC: 50852 AN: 1461840 Hom.: 1429 Cov.: 31 AF XY: 0.0354 AC XY: 25750 AN XY: 727218

African (AFR) AF: 0.00496 AC: 166 AN: 33472

American (AMR) AF: 0.0807 AC: 3610 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0676 AC: 1766 AN: 26134

East Asian (EAS) AF: 0.140 AC: 5554 AN: 39698

South Asian (SAS) AF: 0.0497 AC: 4287 AN: 86254

European-Finnish (FIN) AF: 0.0113 AC: 603 AN: 53420

Middle Eastern (MID) AF: 0.0409 AC: 236 AN: 5768

European-Non Finnish (NFE) AF: 0.0292 AC: 32489 AN: 1111982

Other (OTH) AF: 0.0354 AC: 2141 AN: 60396

GnomAD4 genome AF: 0.0309 AC: 4692 AN: 152088 Hom.: 133 Cov.: 32 AF XY: 0.0309 AC XY: 2297 AN XY: 74356

African (AFR) AF: 0.00672 AC: 279 AN: 41490

American (AMR) AF: 0.0530 AC: 810 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.0724 AC: 251 AN: 3468

East Asian (EAS) AF: 0.139 AC: 719 AN: 5156

South Asian (SAS) AF: 0.0568 AC: 273 AN: 4806

European-Finnish (FIN) AF: 0.0101 AC: 107 AN: 10580

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0317 AC: 2155 AN: 67996

Other (OTH) AF: 0.0298 AC: 63 AN: 2112

Alfa AF: 0.0344 Hom.: 512

Bravo AF: 0.0346

TwinsUK AF: 0.0313 AC: 116

ALSPAC AF: 0.0353 AC: 136

ESP6500AA AF: 0.00885 AC: 39

ESP6500EA AF: 0.0317 AC: 273

ExAC AF: 0.0447 AC: 5424

Asia WGS AF: 0.100 AC: 348 AN: 3478

EpiCase AF: 0.0302

EpiControl AF: 0.0346

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.73	D;D
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	.;D
MetaRNN	Benign	0.0026	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Uncertain	2.6	M;M
PhyloP100		7.8
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-3.0	D;D
REVEL	Benign	0.25
Sift	Uncertain	0.018	D;D
Sift4G	Uncertain	0.011	D;D
Polyphen		0.39	B;B
Vest4		0.56
MPC		0.98
ClinPred		0.046	T
GERP RS		5.5
Varity_R		0.25
gMVP		0.83
Mutation Taster		=90/10	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4148254; hg19: chr4-115544713; COSMIC: COSV60419875; COSMIC: COSV60419875;