17-50353638-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_022167.4(XYLT2):c.144G>T(p.Arg48Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000283 in 1,412,276 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: XYLT2 NM_022167.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.898

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14772043).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
XYLT2	NM_022167.4	c.144G>T	p.Arg48Ser	missense_variant	2/11	ENST00000017003.7
XYLT2	XM_005257572.5	c.48G>T	p.Arg16Ser	missense_variant	2/11
XYLT2	XM_047436522.1	c.-448G>T		5_prime_UTR_variant	2/11
XYLT2	NR_110010.2	n.159G>T		non_coding_transcript_exon_variant	2/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
XYLT2	ENST00000017003.7	c.144G>T	p.Arg48Ser	missense_variant	2/11	1	NM_022167.4	P1
XYLT2	ENST00000376550.7	c.144G>T	p.Arg48Ser	missense_variant, NMD_transcript_variant	2/10	1
XYLT2	ENST00000507602.5	c.144G>T	p.Arg48Ser	missense_variant	2/10	2
XYLT2	ENST00000509778.1	c.99G>T	p.Arg33Ser	missense_variant	2/2	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000231 AC: 4 AN: 173288 Hom.: 0 AF XY: 0.0000215 AC XY: 2 AN XY: 92836

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000112

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000755

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000283 AC: 4 AN: 1412276 Hom.: 0 Cov.: 31 AF XY: 0.00000287 AC XY: 2 AN XY: 698034

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000106

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000882 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000842 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 23, 2022

This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 48 of the XYLT2 protein (p.Arg48Ser). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with XYLT2-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

XYLT2-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 02, 2024

The XYLT2 c.144G>T variant is predicted to result in the amino acid substitution p.Arg48Ser. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.011% of alleles in individuals of Latino descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.054	T
BayesDel_noAF	Benign	-0.31
Cadd	Benign	21
Dann	Benign	0.96
DEOGEN2	Benign	0.12	T;.;.
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.69
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.84	T;T;T
M_CAP	Uncertain	0.23	D
MetaRNN	Benign	0.15	T;T;T
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	1.9	L;.;.
MutationTaster	Benign	0.92	D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-1.8	N;D;N
REVEL	Benign	0.15
Sift	Uncertain	0.010	D;D;D
Sift4G	Benign	0.20	T;D;T
Polyphen		0.98	D;.;.
Vest4		0.49
MutPred		0.20		Gain of phosphorylation at R48 (P = 0.0056);.;Gain of phosphorylation at R48 (P = 0.0056);
MVP		0.29
MPC		1.1
ClinPred		0.38	T
GERP RS		-1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.25
gMVP		0.41

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs777339294; hg19: chr17-48430999;