rs61758388

chr16-17470454-C-Achr16-17470454-C-Gchr16-17470454-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_022166.4(XYLT1):c.343G>T(p.Ala115Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0268 in 1,230,650 control chromosomes in the GnomAD database, including 523 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (49 hom., cov: 31)
  • Exomes 𝑓: 0.028 (474 hom.)
• Consequence: XYLT1 NM_022166.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3 O:1
• Conservation: PhyloP100: 0.397

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]

LOC107987234 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013451189).
• BP6: Variant 16-17470454-C-A is Benign according to our data. Variant chr16-17470454-C-A is described in ClinVar as [Benign]. Clinvar id is 2534.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-17470454-C-A is described in Lovd as [Benign]. Variant chr16-17470454-C-A is described in Lovd as [Likely_benign]. Variant chr16-17470454-C-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0187 (2844/151954) while in subpopulation NFE AF= 0.0293 (1989/67872). AF 95% confidence interval is 0.0282. There are 49 homozygotes in gnomad4. There are 1313 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 49 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
XYLT1	NM_022166.4	c.343G>T	p.Ala115Ser	missense_variant	1/12	ENST00000261381.7
XYLT1	XM_047434458.1	c.343G>T	p.Ala115Ser	missense_variant	1/11
XYLT1	XM_017023539.3	c.343G>T	p.Ala115Ser	missense_variant	1/12
LOC107987234	XR_001752091.2			upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
XYLT1	ENST00000261381.7	c.343G>T	p.Ala115Ser	missense_variant	1/12	1	NM_022166.4	P1

Frequencies

GnomAD3 genomes AF: 0.0187 AC: 2845 AN: 151840 Hom.: 49 Cov.: 31

Gnomad AFR AF: 0.00524

Gnomad AMI AF: 0.0747

Gnomad AMR AF: 0.0182

Gnomad ASJ AF: 0.0346

Gnomad EAS AF: 0.000195

Gnomad SAS AF: 0.00518

Gnomad FIN AF: 0.00890

Gnomad MID AF: 0.0191

Gnomad NFE AF: 0.0293

Gnomad OTH AF: 0.0225

GnomAD3 exomes AF: 0.0273 AC: 27 AN: 988 Hom.: 0 AF XY: 0.0234 AC XY: 13 AN XY: 556

Gnomad AFR exome AF: 0.0250

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0357

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0297

Gnomad OTH exome AF: 0.0294

GnomAD4 exome AF: 0.0280 AC: 30184 AN: 1078696 Hom.: 474 Cov.: 30 AF XY: 0.0279 AC XY: 14220 AN XY: 510138

Gnomad4 AFR exome AF: 0.00374

Gnomad4 AMR exome AF: 0.0114

Gnomad4 ASJ exome AF: 0.0329

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00455

Gnomad4 FIN exome AF: 0.00807

Gnomad4 NFE exome AF: 0.0307

Gnomad4 OTH exome AF: 0.0238

GnomAD4 genome AF: 0.0187 AC: 2844 AN: 151954 Hom.: 49 Cov.: 31 AF XY: 0.0177 AC XY: 1313 AN XY: 74270

Gnomad4 AFR AF: 0.00522

Gnomad4 AMR AF: 0.0181

Gnomad4 ASJ AF: 0.0346

Gnomad4 EAS AF: 0.000196

Gnomad4 SAS AF: 0.00518

Gnomad4 FIN AF: 0.00890

Gnomad4 NFE AF: 0.0293

Gnomad4 OTH AF: 0.0223

Alfa AF: 0.0119 Hom.: 2

Bravo AF: 0.0181

ExAC AF: 0.00598 AC: 316

Asia WGS AF: 0.00289 AC: 10 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Desbuquois dysplasia 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Desbuquois dysplasia 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 30, 2020

This variant is associated with the following publications: (PMID: 19014925, 16759312, 16571645) -

Pseudoxanthoma elasticum, modifier of severity of Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Sep 01, 2006

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.75
Cadd	Benign	16
Dann	Uncertain	0.98
DEOGEN2	Benign	0.0093	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.36	N
MetaRNN	Benign	0.013	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	0.051	A
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-0.010	N
REVEL	Benign	0.021
Sift	Benign	0.41	T
Sift4G	Benign	0.50	T
Polyphen		0.0010	B
Vest4		0.024
MPC		0.20
ClinPred		0.0042	T
GERP RS		1.8
Varity_R		0.082
gMVP		0.12

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

LitVar

Other links and lift over

dbSNP: rs61758388; hg19: chr16-17564311; COSMIC: COSV54477311;