dbSNP rs587777369: XYLT1:p.Gln94ArgfsTer100 (chr16-17470520-GC-G) – ACMG Classification: Pathogenic (10 pts)

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1PM2

The NM_022166.4(XYLT1):c.276delG(p.Gln94ArgfsTer100) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 9.3e-7 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

XYLT1
NM_022166.4 frameshift

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.366

Publications

2 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
XYLT1	NM_022166.4 link	c.276delG	p.Gln94ArgfsTer100	frameshift_variant	Exon 1 of 12	ENST00000261381.7	NP_071449.1
XYLT1	XM_047434458.1 link	c.276delG	p.Gln94ArgfsTer87	frameshift_variant	Exon 1 of 11		XP_047290414.1
XYLT1	XM_017023539.3 link	c.276delG	p.Gln94ArgfsTer100	frameshift_variant	Exon 1 of 12		XP_016879028.1
LOC107987234	XR_001752091.2 link	n.-94delG		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
XYLT1	ENST00000261381.7 link	c.276delG	p.Gln94ArgfsTer100	frameshift_variant	Exon 1 of 12	1	NM_022166.4	ENSP00000261381.6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

488

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

9.29e-7

AC:

AN:

1076760

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

509236

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

22680

American (AMR)

AF:

0.00

AC:

AN:

8220

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

14104

East Asian (EAS)

AF:

0.00

AC:

AN:

26292

South Asian (SAS)

AF:

0.00

AC:

AN:

19702

European-Finnish (FIN)

AF:

0.00

AC:

AN:

21072

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2922

European-Non Finnish (NFE)

AF:

0.00000109

AC:

AN:

918506

Other (OTH)

AF:

0.00

AC:

AN:

43262

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

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

PhyloP100

-0.37

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