chr16-17138534-G-A

Position:

chr16-17138534-G-A

Variant summary

Our verdict is Benign. Variant got -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

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:

ENSG00000261448 (HGNC:):

ENSG00000261448 links:

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ACMG classification

Classification made for transcript

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	Effect	#exon/exons	MANE	Protein	UniProt
XYLT1	NM_022166.4 linkuse as main transcript	c.1588-3C>T	splice_region_variant, intron_variant		ENST00000261381.7	NP_071449.1	Q86Y38
XYLT1	XM_047434458.1 linkuse as main transcript	c.1549-3C>T	splice_region_variant, intron_variant			XP_047290414.1
XYLT1	XM_017023539.3 linkuse as main transcript	c.1588-3C>T	splice_region_variant, intron_variant			XP_016879028.1
LOC102723692	NR_135179.1 linkuse as main transcript	n.439G>A	non_coding_transcript_exon_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
XYLT1	ENST00000261381.7 linkuse as main transcript	c.1588-3C>T		splice_region_variant, intron_variant		1	NM_022166.4	ENSP00000261381.6		Q86Y38
ENSG00000261448	ENST00000567344.1 linkuse as main transcript	n.439G>A		non_coding_transcript_exon_variant	3/3	3

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

GnomAD3 exomes

AF:

0.00177

AC:

443

AN:

250824

Hom.:

AF XY:

0.00179

AC XY:

242

AN XY:

135538

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 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.:

Cov.:

AF XY:

0.00208

AC XY:

1510

AN XY:

726320

show subpopulations

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.:

Cov.:

AF XY:

0.00136

AC XY:

101

AN XY:

74340

show subpopulations

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.:

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

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	XYLT1: BP4, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
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	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Desbuquois dysplasia 2

Pathogenic:1Uncertain: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

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

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