16-17109015-C-T

Variant summary

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

The NM_022166.4(XYLT1):c.2560G>A(p.Glu854Lys) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000739 in 1,353,524 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E854A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.4e-7 (0 hom.)
• Consequence: XYLT1 NM_022166.4 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.71

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 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=0.2622698).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
XYLT1	NM_022166.4	c.2560G>A	p.Glu854Lys	missense_variant, splice_region_variant	12/12	ENST00000261381.7
XYLT1	XM_047434458.1	c.2521G>A	p.Glu841Lys	missense_variant, splice_region_variant	11/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
XYLT1	ENST00000261381.7	c.2560G>A	p.Glu854Lys	missense_variant, splice_region_variant	12/12	1	NM_022166.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000110 AC: 2 AN: 181890 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 95564

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000898

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

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: 7.39e-7 AC: 1 AN: 1353524 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 659680

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000304

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

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Desbuquois dysplasia 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

May 01, 2023

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. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant  is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 1407331). This variant has not been reported in the literature in individuals affected with XYLT1-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.009%). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 854 of the XYLT1 protein (p.Glu854Lys). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.47
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Benign	0.032	T
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.94	D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.2	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.14
Sift	Benign	0.26	T
Sift4G	Benign	0.28	T
Polyphen		0.94	P
Vest4		0.29
MutPred		0.53		Loss of ubiquitination at K851 (P = 0.0103);
MVP		0.21
MPC		0.42
ClinPred		0.68	D
GERP RS		5.8
Varity_R		0.33
gMVP		0.49

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs769391314; hg19: chr16-17202872; COSMIC: COSV105044329;