16-17470643-C-T

Variant names:

• chr16-17470643-C-T
• rs766521030
• NM_022166.4:c.154G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

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. 14/21 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
• Publications: 0 publications found

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

LOC107987234 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -13 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 VariationId is 577084.
• 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 the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 6 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022166.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XYLT1	NM_022166.4	MANE Select	c.154G>A	p.Gly52Ser	missense	Exon 1 of 12	NP_071449.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XYLT1	ENST00000261381.7	TSL:1 MANE Select	c.154G>A	p.Gly52Ser	missense	Exon 1 of 12	ENSP00000261381.6

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

GnomAD2 exomes AF: 0.00119 AC: 49 AN: 41118 AF XY: 0.00120

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 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

African (AFR) AF: 0.000219 AC: 4 AN: 18238

American (AMR) AF: 0.000195 AC: 2 AN: 10272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10340

East Asian (EAS) AF: 0.00 AC: 0 AN: 7314

South Asian (SAS) AF: 0.00199 AC: 73 AN: 36696

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9100

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2176

European-Non Finnish (NFE) AF: 0.00149 AC: 1244 AN: 837258

Other (OTH) AF: 0.00131 AC: 44 AN: 33496

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

African (AFR) AF: 0.000562 AC: 23 AN: 40940

American (AMR) AF: 0.000202 AC: 3 AN: 14834

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3390

East Asian (EAS) AF: 0.00 AC: 0 AN: 4946

South Asian (SAS) AF: 0.00167 AC: 8 AN: 4792

European-Finnish (FIN) AF: 0.000114 AC: 1 AN: 8752

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 288

European-Non Finnish (NFE) AF: 0.00149 AC: 98 AN: 65978

Other (OTH) AF: 0.000489 AC: 1 AN: 2046

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

Jul 24, 2019

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Dec 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

XYLT1-related disorder Benign:1

May 23, 2022

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 v4.9

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
PhyloP100		0.11
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
PromoterAI		-0.033	Neutral
Varity_R		0.084
gMVP		0.30
Mutation Taster		=95/5	polymorphism

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

Other links and lift over

dbSNP: rs766521030; hg19: chr16-17564500;