17-50353660-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_022167.4(XYLT2):c.166G>A(p.Asp56Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0135 in 1,566,816 control chromosomes in the GnomAD database, including 183 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.010 (14 hom., cov: 32)
  • Exomes 𝑓: 0.014 (169 hom.)
• Consequence: XYLT2 NM_022167.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 6.71

Genes affected

XYLT2 (HGNC:15517): (xylosyltransferase 2) The protein encoded by this gene is an isoform of xylosyltransferase, which belongs to a family of glycosyltransferases. This enzyme transfers xylose from UDP-xylose to specific serine residues of the core protein and initiates the biosynthesis of glycosaminoglycan chains in proteoglycans including chondroitin sulfate, heparan sulfate, heparin and dermatan sulfate. The enzyme activity, which is increased in scleroderma patients, is a diagnostic marker for the determination of sclerotic activity in systemic sclerosis. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Dec 2013]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004224777).
• BP6: Variant 17-50353660-G-A is Benign according to our data. Variant chr17-50353660-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 1299780.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-50353660-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0101 (1541/152272) while in subpopulation NFE AF= 0.0154 (1045/68008). AF 95% confidence interval is 0.0146. There are 14 homozygotes in gnomad4. There are 704 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 14 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
XYLT2	NM_022167.4	c.166G>A	p.Asp56Asn	missense_variant	2/11	ENST00000017003.7
XYLT2	XM_005257572.5	c.70G>A	p.Asp24Asn	missense_variant	2/11
XYLT2	XM_047436522.1	c.-426G>A		5_prime_UTR_variant	2/11
XYLT2	NR_110010.2	n.181G>A		non_coding_transcript_exon_variant	2/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
XYLT2	ENST00000017003.7	c.166G>A	p.Asp56Asn	missense_variant	2/11	1	NM_022167.4	P1
XYLT2	ENST00000376550.7	c.166G>A	p.Asp56Asn	missense_variant, NMD_transcript_variant	2/10	1
XYLT2	ENST00000507602.5	c.166G>A	p.Asp56Asn	missense_variant	2/10	2
XYLT2	ENST00000509778.1	c.121G>A	p.Asp41Asn	missense_variant	2/2	3

Frequencies

GnomAD3 genomes AF: 0.0101 AC: 1540 AN: 152154 Hom.: 14 Cov.: 32

Gnomad AFR AF: 0.00292

Gnomad AMI AF: 0.0241

Gnomad AMR AF: 0.0105

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.0130

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0154

Gnomad OTH AF: 0.0120

GnomAD3 exomes AF: 0.00927 AC: 1626 AN: 175480 Hom.: 16 AF XY: 0.00958 AC XY: 898 AN XY: 93782

Gnomad AFR exome AF: 0.00283

Gnomad AMR exome AF: 0.00549

Gnomad ASJ exome AF: 0.00342

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00295

Gnomad FIN exome AF: 0.0131

Gnomad NFE exome AF: 0.0151

Gnomad OTH exome AF: 0.0135

GnomAD4 exome AF: 0.0138 AC: 19587 AN: 1414544 Hom.: 169 Cov.: 32 AF XY: 0.0136 AC XY: 9480 AN XY: 699316

Gnomad4 AFR exome AF: 0.00250

Gnomad4 AMR exome AF: 0.00714

Gnomad4 ASJ exome AF: 0.00276

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00300

Gnomad4 FIN exome AF: 0.0129

Gnomad4 NFE exome AF: 0.0162

Gnomad4 OTH exome AF: 0.0112

GnomAD4 genome AF: 0.0101 AC: 1541 AN: 152272 Hom.: 14 Cov.: 32 AF XY: 0.00945 AC XY: 704 AN XY: 74464

Gnomad4 AFR AF: 0.00291

Gnomad4 AMR AF: 0.0105

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00207

Gnomad4 FIN AF: 0.0130

Gnomad4 NFE AF: 0.0154

Gnomad4 OTH AF: 0.0118

Alfa AF: 0.0143 Hom.: 19

Bravo AF: 0.0101

TwinsUK AF: 0.0183 AC: 68

ALSPAC AF: 0.0184 AC: 71

ESP6500AA AF: 0.00364 AC: 16

ESP6500EA AF: 0.0137 AC: 118

ExAC AF: 0.00654 AC: 777

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Osteogenesis imperfecta Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Apr 11, 2022

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

XYLT2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 19, 2019

This variant is classified as 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	0.12
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.48
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Benign	0.065	T;.;.
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.051
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.87	D;D;D
MetaRNN	Benign	0.0042	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-1.6	N;D;N
REVEL	Benign	0.14
Sift	Benign	0.20	T;D;T
Sift4G	Benign	0.29	T;T;T
Polyphen		0.0050	B;.;.
Vest4		0.22
MVP		0.31
MPC		0.43
ClinPred		0.023	T
GERP RS		4.4
Varity_R		0.092
gMVP		0.25

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs113835371; hg19: chr17-48431021; COSMIC: COSV99059977; COSMIC: COSV99059977;