rs201818754

Positions:

• chr16-17138534-G-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_022166.4(XYLT1):​c.1588-3C>T variant causes a splice region, splice polypyrimidine tract, 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, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.002965
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts P:1 U:1 B:8
• Conservation: PhyloP100: 6.61

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -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. Variant chr16-17138534-G-A is described in Lovd as [Likely_pathogenic].
• 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
XYLT1	NM_022166.4	c.1588-3C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000261381.7	NP_071449.1
LOC102723692	NR_135179.1	n.439G>A		non_coding_transcript_exon_variant	3/3
XYLT1	XM_017023539.3	c.1588-3C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			XP_016879028.1
XYLT1	XM_047434458.1	c.1549-3C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			XP_047290414.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
XYLT1	ENST00000261381.7	c.1588-3C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_022166.4	ENSP00000261381	P1
	ENST00000567344.1	n.439G>A		non_coding_transcript_exon_variant	3/3	3

Frequencies

GnomAD3 genomes AF: 0.00140 AC: 212 AN: 151968 Hom.: 0 Cov.: 32

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

GnomAD3 exomes AF: 0.00177 AC: 443 AN: 250824 Hom.: 3 AF XY: 0.00179 AC XY: 242 AN XY: 135538

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 SAS exome AF: 0.00203

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.: 9 Cov.: 31 AF XY: 0.00208 AC XY: 1510 AN XY: 726320

Gnomad4 AFR exome AF: 0.000508

Gnomad4 AMR exome AF: 0.000828

Gnomad4 ASJ exome AF: 0.00613

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00225

Gnomad4 FIN exome AF: 0.000356

Gnomad4 NFE exome AF: 0.00206

Gnomad4 OTH exome AF: 0.00219

GnomAD4 genome AF: 0.00139 AC: 212 AN: 152090 Hom.: 0 Cov.: 32 AF XY: 0.00136 AC XY: 101 AN XY: 74340

Gnomad4 AFR AF: 0.000458

Gnomad4 AMR AF: 0.000916

Gnomad4 ASJ AF: 0.00692

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00208

Gnomad4 FIN AF: 0.000282

Gnomad4 NFE AF: 0.00203

Gnomad4 OTH AF: 0.000948

Alfa AF: 0.00209 Hom.: 0

Bravo AF: 0.00132

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00213

EpiControl AF: 0.00267

ClinVar

Significance: Likely benign

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

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 29, 2020	This variant is associated with the following publications: (PMID: 31589614, 30919572, 24581741, 28462984, 27881841) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	XYLT1: BP4, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Desbuquois dysplasia 2 Pathogenic:1 Uncertain:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 06, 2014	- -
Uncertain significance, no assertion criteria provided	curation	Reproductive Health Research and Development, BGI Genomics	Jan 06, 2020	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

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 17, 2024

- -

Autosomal recessive inherited pseudoxanthoma elasticum;C4014294:Desbuquois dysplasia 2 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 26, 2021

- -

XYLT1-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 12, 2024

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	15
DANN	Benign	0.81
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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

LitVar

Other links and lift over

dbSNP: rs201818754; hg19: chr16-17232391;