rs139179946

Positions:

chr16-17138363-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BS1_Supporting

The NM_022166.4(XYLT1):c.1756C>T(p.Arg586Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000271 in 1,611,566 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00023 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00027 ( 0 hom. )

Consequence

XYLT1
NM_022166.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 3.53

Variant links:

Genes affected

XYLT1 (HGNC:15516): (xylosyltransferase 1) This locus encodes a xylosyltransferase enzyme. The encoded protein catalyzes transfer of UDP-xylose to serine residues of an acceptor protein substrate. This transfer reaction is necessary for biosynthesis of glycosaminoglycan chains. Mutations in this gene have been associated with increased severity of pseudoxanthoma elasticum.[provided by RefSeq, Nov 2009]

XYLT1 links:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00023 (35/152288) while in subpopulation SAS AF= 0.000622 (3/4822). AF 95% confidence interval is 0.00026. There are 0 homozygotes in gnomad4. There are 16 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
XYLT1	NM_022166.4 linkuse as main transcript	c.1756C>T	p.Arg586Cys	missense_variant	8/12	ENST00000261381.7
LOC102723692	NR_135179.1 linkuse as main transcript	n.268G>A		non_coding_transcript_exon_variant	3/3
XYLT1	XM_047434458.1 linkuse as main transcript	c.1717C>T	p.Arg573Cys	missense_variant	7/11
XYLT1	XM_017023539.3 linkuse as main transcript	c.1756C>T	p.Arg586Cys	missense_variant	8/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
XYLT1	ENST00000261381.7 linkuse as main transcript	c.1756C>T	p.Arg586Cys	missense_variant	8/12	1	NM_022166.4	P1
	ENST00000567344.1 linkuse as main transcript	n.268G>A		non_coding_transcript_exon_variant	3/3	3

Frequencies

GnomAD3 genomes

AF:

0.000217

AC:

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000524

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000622

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000191

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.000239

AC:

AN:

251082

Hom.:

AF XY:

0.000265

AC XY:

AN XY:

135670

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.000318

Gnomad ASJ exome

AF:

0.0000994

Gnomad EAS exome

AF:

0.000272

Gnomad SAS exome

AF:

0.000294

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000275

AC:

401

AN:

1459278

Hom.:

Cov.:

AF XY:

0.000274

AC XY:

199

AN XY:

725452

show subpopulations

Gnomad4 AFR exome

AF:

0.000449

Gnomad4 AMR exome

AF:

0.000269

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.000404

Gnomad4 SAS exome

AF:

0.000348

Gnomad4 FIN exome

AF:

0.0000374

Gnomad4 NFE exome

AF:

0.000272

Gnomad4 OTH exome

AF:

0.000365

GnomAD4 genome

AF:

0.000230

AC:

AN:

152288

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.000144

Gnomad4 AMR

AF:

0.000523

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.000622

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.000191

Gnomad4 OTH

AF:

0.000949

Alfa

AF:

0.000255

Hom.:

Bravo

AF:

0.000268

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.000280

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.000218

EpiControl

AF:

0.000415

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Desbuquois dysplasia 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 12, 2022

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 586 of the XYLT1 protein (p.Arg586Cys). This variant is present in population databases (rs139179946, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with XYLT1-related conditions. ClinVar contains an entry for this variant (Variation ID: 573227). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt XYLT1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Autosomal recessive inherited pseudoxanthoma elasticum;C4014294:Desbuquois dysplasia 2

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Benign

-0.011

BayesDel_noAF

Uncertain

0.050

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.44

Eigen

Pathogenic

0.76

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Benign

0.74

M_CAP

Benign

0.068

MetaRNN

Uncertain

0.73

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.8

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.84

PROVEAN

Pathogenic

-7.4

REVEL

Uncertain

0.32

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.89

MVP

0.23

MPC

0.98

ClinPred

0.69

GERP RS

4.7

Varity_R

0.89

gMVP

0.82

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over