chr16-17109015-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_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

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.71

Publications

1 publications found

Variant links:

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

XYLT1 links:

ENSG00000261448 (HGNC:):

ENSG00000261448 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 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 rank	MANE	Protein	UniProt
XYLT1	NM_022166.4 link	c.2560G>A	p.Glu854Lys	missense_variant, splice_region_variant	Exon 12 of 12	ENST00000261381.7	NP_071449.1	Q86Y38
XYLT1	XM_047434458.1 link	c.2521G>A	p.Glu841Lys	missense_variant, splice_region_variant	Exon 11 of 11		XP_047290414.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
XYLT1	ENST00000261381.7 link	c.2560G>A	p.Glu854Lys	missense_variant, splice_region_variant	Exon 12 of 12	1	NM_022166.4	ENSP00000261381.6		Q86Y38

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000110

AC:

AN:

181890

AF XY:

0.00

show subpopulations

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

7.39e-7

AC:

AN:

1353524

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

659680

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30904

American (AMR)

AF:

0.0000304

AC:

AN:

32856

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20718

East Asian (EAS)

AF:

0.00

AC:

AN:

37982

South Asian (SAS)

AF:

0.00

AC:

AN:

66638

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47464

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5310

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1055640

Other (OTH)

AF:

0.00

AC:

AN:

56012

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Desbuquois dysplasia 1

Uncertain:1

May 01, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

BayesDel_noAF

Benign

-0.47

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.032

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Uncertain

0.94

M_CAP

Benign

0.012

MetaRNN

Benign

0.26

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.2

PhyloP100

7.7

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-1.9

REVEL

Benign

0.14

Sift

Benign

0.26

Sift4G

Benign

0.28

Polyphen

0.94

Vest4

0.29

MutPred

0.53

Loss of ubiquitination at K851 (P = 0.0103);

MVP

0.21

MPC

0.42

ClinPred

0.68

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over