rs766521030

chr16-17470643-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_022166.4(XYLT1):c.154G>A(p.Gly52Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00135 in 1,111,762 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00091 (1 hom., cov: 30)
  • Exomes 𝑓: 0.0014 (6 hom.)
• Consequence: XYLT1 NM_022166.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 0.110

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]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004581392).
• BP6: Variant 16-17470643-C-T is Benign according to our data. Variant chr16-17470643-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 577084.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}. Variant chr16-17470643-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000912 (134/146872) while in subpopulation SAS AF= 0.00167 (8/4792). AF 95% confidence interval is 0.00125. There are 1 homozygotes in gnomad4. There are 62 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
XYLT1	NM_022166.4	c.154G>A	p.Gly52Ser	missense_variant	1/12	ENST00000261381.7
XYLT1	XM_047434458.1	c.154G>A	p.Gly52Ser	missense_variant	1/11
XYLT1	XM_017023539.3	c.154G>A	p.Gly52Ser	missense_variant	1/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
XYLT1	ENST00000261381.7	c.154G>A	p.Gly52Ser	missense_variant	1/12	1	NM_022166.4	P1

Frequencies

GnomAD3 genomes AF: 0.000913 AC: 134 AN: 146762 Hom.: 1 Cov.: 30

Gnomad AFR AF: 0.000563

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000203

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00167

Gnomad FIN AF: 0.000114

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00149

Gnomad OTH AF: 0.000494

GnomAD3 exomes AF: 0.00119 AC: 49 AN: 41118 Hom.: 0 AF XY: 0.00120 AC XY: 30 AN XY: 24930

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000149

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00232

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00155

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00142 AC: 1367 AN: 964890 Hom.: 6 Cov.: 29 AF XY: 0.00144 AC XY: 669 AN XY: 466032

Gnomad4 AFR exome AF: 0.000219

Gnomad4 AMR exome AF: 0.000195

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00199

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00149

Gnomad4 OTH exome AF: 0.00131

GnomAD4 genome AF: 0.000912 AC: 134 AN: 146872 Hom.: 1 Cov.: 30 AF XY: 0.000867 AC XY: 62 AN XY: 71498

Gnomad4 AFR AF: 0.000562

Gnomad4 AMR AF: 0.000202

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00167

Gnomad4 FIN AF: 0.000114

Gnomad4 NFE AF: 0.00149

Gnomad4 OTH AF: 0.000489

Alfa AF: 0.00171 Hom.: 1

Bravo AF: 0.000706

ExAC AF: 0.000874 AC: 15

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jul 24, 2019

In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; In silico analysis, which includes splice predictors and evolutionary conservation, suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Has not been previously published as pathogenic or benign to our knowledge -

Desbuquois dysplasia 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 08, 2024

- -

XYLT1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 23, 2022

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
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.70
Cadd	Benign	18
Dann	Benign	0.96
DEOGEN2	Benign	0.012	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.039	N
MetaRNN	Benign	0.0046	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	1.0	N
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-0.020	N
REVEL	Benign	0.027
Sift	Benign	0.20	T
Sift4G	Benign	0.65	T
Polyphen		0.0020	B
Vest4		0.074
MVP		0.068
MPC		0.22
ClinPred		0.014	T
GERP RS		0.46
Varity_R		0.084
gMVP		0.30

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

Other links and lift over

dbSNP: rs766521030; hg19: chr16-17564500;