rs201818754

Variant names:

• chr16-17138534-G-A
• rs201818754
• NM_022166.4:c.1588-3C>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_022166.4(XYLT1):​c.1588-3C>T variant causes a splice region, intron change. The variant allele was found at a frequency of 0.00193 in 1,612,642 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (9 hom.)
• Consequence: XYLT1 NM_022166.4 splice_region, intron
• Scores: Splicing: ADA: 0.002965
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts P:1 U:1 B:9
• Conservation: PhyloP100: 6.61
• Publications: 2 publications found

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

ENSG00000261448 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 16-17138534-G-A is Benign according to our data. Variant chr16-17138534-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 127238.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00139 (212/152090) while in subpopulation SAS AF = 0.00208 (10/4812). AF 95% confidence interval is 0.00175. There are 0 homozygotes in GnomAd4. There are 101 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 9 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022166.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XYLT1	NM_022166.4	MANE Select	c.1588-3C>T		splice_region intron	N/A	NP_071449.1
	LOC102723692	NR_135179.1		n.439G>A		non_coding_transcript_exon	Exon 3 of 3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XYLT1	ENST00000261381.7	TSL:1 MANE Select	c.1588-3C>T		splice_region intron	N/A	ENSP00000261381.6
	XYLT1	ENST00000933757.1		c.1588-3C>T		splice_region intron	N/A	ENSP00000603816.1
	ENSG00000261448	ENST00000567344.2	TSL:3	n.825G>A		non_coding_transcript_exon	Exon 5 of 5

Frequencies

GnomAD3 genomes AF: 0.00140 AC: 212 AN: 151968 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000459

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000917

Gnomad ASJ AF: 0.00692

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00208

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00203

Gnomad OTH AF: 0.000958

GnomAD2 exomes AF: 0.00177 AC: 443 AN: 250824 AF XY: 0.00179

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.00101

Gnomad ASJ exome AF: 0.00556

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000324

Gnomad NFE exome AF: 0.00233

Gnomad OTH exome AF: 0.00261

GnomAD4 exome AF: 0.00199 AC: 2905 AN: 1460552 Hom.: 9 Cov.: 31 AF XY: 0.00208 AC XY: 1510 AN XY: 726320

African (AFR) AF: 0.000508 AC: 17 AN: 33446

American (AMR) AF: 0.000828 AC: 37 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.00613 AC: 160 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39646

South Asian (SAS) AF: 0.00225 AC: 194 AN: 86240

European-Finnish (FIN) AF: 0.000356 AC: 19 AN: 53400

Middle Eastern (MID) AF: 0.00961 AC: 55 AN: 5724

European-Non Finnish (NFE) AF: 0.00206 AC: 2291 AN: 1110922

Other (OTH) AF: 0.00219 AC: 132 AN: 60350

GnomAD4 genome AF: 0.00139 AC: 212 AN: 152090 Hom.: 0 Cov.: 32 AF XY: 0.00136 AC XY: 101 AN XY: 74340

African (AFR) AF: 0.000458 AC: 19 AN: 41526

American (AMR) AF: 0.000916 AC: 14 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00692 AC: 24 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5030

South Asian (SAS) AF: 0.00208 AC: 10 AN: 4812

European-Finnish (FIN) AF: 0.000282 AC: 3 AN: 10628

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00203 AC: 138 AN: 68024

Other (OTH) AF: 0.000948 AC: 2 AN: 2110

Alfa AF: 0.00209 Hom.: 0

Bravo AF: 0.00132

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00213

EpiControl AF: 0.00267

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
1	1	-	Desbuquois dysplasia 2 (2)
-	-	1	Autosomal recessive inherited pseudoxanthoma elasticum;C4014294:Desbuquois dysplasia 2 (1)
-	-	1	Desbuquois dysplasia 1 (1)
-	-	1	not specified (1)
-	-	1	XYLT1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	15
DANN	Benign	0.81
PhyloP100		6.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0030
dbscSNV1_RF	Benign	0.036
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

Other links and lift over

dbSNP: rs201818754; hg19: chr16-17232391;