rs201818754

Variant names:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBS1BS2

The NM_022166.4(XYLT1):c.1588-3C>T variant causes a splice region, intron change. The variant allele was found at a frequency of 0.00193 in 1,612,642 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0020 ( 9 hom. )

Consequence

XYLT1
NM_022166.4 splice_region, intron

Scores

Splicing: ADA: 0.002965

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts P:1U:1B:8

Conservation

PhyloP100: 6.61

Publications

2 publications found

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 Gene-Disease associations (from GenCC):

Desbuquois dysplasia 2
Inheritance: AR Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
Desbuquois dysplasia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
XYLT1-congenital disorder of glycosylation
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

XYLT1 links:

ENSG00000261448 (HGNC:):

ENSG00000261448 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.41).

BP6

Variant 16-17138534-G-A is Benign according to our data. Variant chr16-17138534-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 127238.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00139 (212/152090) while in subpopulation SAS AF = 0.00208 (10/4812). AF 95% confidence interval is 0.00175. There are 0 homozygotes in GnomAd4. There are 101 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
XYLT1	NM_022166.4 link	c.1588-3C>T	splice_region_variant, intron_variant	Intron 7 of 11	ENST00000261381.7	NP_071449.1	Q86Y38
LOC102723692	NR_135179.1 link	n.439G>A	non_coding_transcript_exon_variant	Exon 3 of 3
XYLT1	XM_047434458.1 link	c.1549-3C>T	splice_region_variant, intron_variant	Intron 6 of 10		XP_047290414.1
XYLT1	XM_017023539.3 link	c.1588-3C>T	splice_region_variant, intron_variant	Intron 7 of 11		XP_016879028.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
XYLT1	ENST00000261381.7 link	c.1588-3C>T		splice_region_variant, intron_variant	Intron 7 of 11	1	NM_022166.4	ENSP00000261381.6		Q86Y38

Frequencies

GnomAD3 genomes

AF:

0.00140

AC:

212

AN:

151968

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000459

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000917

Gnomad ASJ

AF:

0.00692

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00208

Gnomad FIN

AF:

0.000282

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00203

Gnomad OTH

AF:

0.000958

GnomAD2 exomes

AF:

0.00177

AC:

443

AN:

250824

AF XY:

0.00179

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.00101

Gnomad ASJ exome

AF:

0.00556

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000324

Gnomad NFE exome

AF:

0.00233

Gnomad OTH exome

AF:

0.00261

GnomAD4 exome

AF:

0.00199

AC:

2905

AN:

1460552

Hom.:

Cov.:

AF XY:

0.00208

AC XY:

1510

AN XY:

726320

show subpopulations

African (AFR)

AF:

0.000508

AC:

AN:

33446

American (AMR)

AF:

0.000828

AC:

AN:

44702

Ashkenazi Jewish (ASJ)

AF:

0.00613

AC:

160

AN:

26122

East Asian (EAS)

AF:

0.00

AC:

AN:

39646

South Asian (SAS)

AF:

0.00225

AC:

194

AN:

86240

European-Finnish (FIN)

AF:

0.000356

AC:

AN:

53400

Middle Eastern (MID)

AF:

0.00961

AC:

AN:

5724

European-Non Finnish (NFE)

AF:

0.00206

AC:

2291

AN:

1110922

Other (OTH)

AF:

0.00219

AC:

132

AN:

60350

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

144

289

433

578

722

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00139

AC:

212

AN:

152090

Hom.:

Cov.:

AF XY:

0.00136

AC XY:

101

AN XY:

74340

show subpopulations

African (AFR)

AF:

0.000458

AC:

AN:

41526

American (AMR)

AF:

0.000916

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00692

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5030

South Asian (SAS)

AF:

0.00208

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.000282

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00203

AC:

138

AN:

68024

Other (OTH)

AF:

0.000948

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00209

Hom.:

Bravo

AF:

0.00132

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00213

EpiControl

AF:

0.00267

ClinVar

Significance: Likely benign

Submissions summary: Pathogenic:1Uncertain:1Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

XYLT1: BP4, BS2 -

Jul 29, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 31589614, 30919572, 24581741, 28462984, 27881841) -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Desbuquois dysplasia 2

Pathogenic:1Uncertain:1

Mar 06, 2014

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Jan 06, 2020

Reproductive Health Research and Development, BGI Genomics

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:curation

NG_015843.1(NM_022166.3):c.1588-3C>T in XYLT1 gene has an allele frequency of 0.006 in Ashkenazi Jewish subpopulation in the gnomAD database. 3 homozygous occurrences are observed in the gnomAD database. This variant has been detected in an individual with Desbuquois dysplasia 2 (PMID: 24581741). Benign computational verdict because benign prediction from DANN. The available evidence is currently insufficient to determine the role of this variant in disease. We interpret it as variant of uncertain significance (VUS). ACMG/AMP criteria applied: PP3; PP4. -

Desbuquois dysplasia 1

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autosomal recessive inherited pseudoxanthoma elasticum;C4014294:Desbuquois dysplasia 2

Benign:1

Nov 26, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

XYLT1-related disorder

Benign:1

Aug 12, 2024

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.41

CADD

Benign

(source)

DANN

Benign

0.81

PhyloP100

6.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Mutation Taster

=98/2

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0030

dbscSNV1_RF

Benign

0.036

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

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rs201818754

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over