16-17138534-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

2
Splicing: ADA: 0.002965
2

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]

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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 HGVSp Effect Exon rank MANE Protein UniProt
XYLT1NM_022166.4 linkc.1588-3C>T splice_region_variant, intron_variant Intron 7 of 11 ENST00000261381.7 NP_071449.1 Q86Y38
XYLT1XM_047434458.1 linkc.1549-3C>T splice_region_variant, intron_variant Intron 6 of 10 XP_047290414.1
XYLT1XM_017023539.3 linkc.1588-3C>T splice_region_variant, intron_variant Intron 7 of 11 XP_016879028.1
LOC102723692NR_135179.1 linkn.439G>A non_coding_transcript_exon_variant Exon 3 of 3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
XYLT1ENST00000261381.7 linkc.1588-3C>T splice_region_variant, intron_variant Intron 7 of 11 1 NM_022166.4 ENSP00000261381.6 Q86Y38
ENSG00000261448ENST00000567344.1 linkn.439G>A non_coding_transcript_exon_variant Exon 3 of 3 3

Frequencies

GnomAD3 genomes
AF:
0.00140
AC:
212
AN:
151968
Hom.:
0
Cov.:
32
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.:
3
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.:
9
Cov.:
31
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.:
0
Cov.:
32
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.:
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:1Uncertain:1Benign:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:5
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 -

-
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Breakthrough Genomics, Breakthrough Genomics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: not provided

- -

-
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

- -

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) -

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
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

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

Other links and lift over

dbSNP: rs201818754; hg19: chr16-17232391; API