Genetic Variant XYLT1:p.Ala115Thr (chr16-17470454-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_022166.4(XYLT1):c.343G>A(p.Ala115Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000927 in 1,078,702 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A115S) has been classified as Benign.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 9.3e-7 ( 0 hom. )

Consequence

XYLT1
NM_022166.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.397

Publications

0 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:

LOC107987234 (HGNC:):

LOC107987234 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.050266534).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
XYLT1	NM_022166.4 link	c.343G>A	p.Ala115Thr	missense_variant	Exon 1 of 12	ENST00000261381.7	NP_071449.1	Q86Y38
XYLT1	XM_047434458.1 link	c.343G>A	p.Ala115Thr	missense_variant	Exon 1 of 11		XP_047290414.1
XYLT1	XM_017023539.3 link	c.343G>A	p.Ala115Thr	missense_variant	Exon 1 of 12		XP_016879028.1
LOC107987234	XR_001752091.2 link	n.-27G>A		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
XYLT1	ENST00000261381.7 link	c.343G>A	p.Ala115Thr	missense_variant	Exon 1 of 12	1	NM_022166.4	ENSP00000261381.6		Q86Y38

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

9.27e-7

AC:

AN:

1078702

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

510140

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

22736

American (AMR)

AF:

0.00

AC:

AN:

8306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

14182

East Asian (EAS)

AF:

0.00

AC:

AN:

26402

South Asian (SAS)

AF:

0.00

AC:

AN:

20234

European-Finnish (FIN)

AF:

0.00

AC:

AN:

21072

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3232

European-Non Finnish (NFE)

AF:

0.00000109

AC:

AN:

919112

Other (OTH)

AF:

0.00

AC:

AN:

43426

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.097

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.77

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0093

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.96

FATHMM_MKL

Benign

0.28

M_CAP

Benign

0.013

MetaRNN

Benign

0.050

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.0

PhyloP100

0.40

PrimateAI

Uncertain

0.77

PROVEAN

Benign

0.19

REVEL

Benign

0.026

Sift

Benign

0.15

Sift4G

Benign

0.47

Polyphen

0.0010

Vest4

0.014

MutPred

0.15

Gain of phosphorylation at A115 (P = 0.0104);

MVP

0.043

MPC

0.21

ClinPred

0.059

GERP RS

1.8

Varity_R

0.070

gMVP

0.11

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over