chr17-50346148-C-A

Variant names:

• chr17-50346148-C-A
• rs1186744711
• NM_022167.4:c.8C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP3 BP4

The NM_022167.4(XYLT2):​c.8C>A​(p.Ala3Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000000901 in 1,109,508 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. A3V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 9.0e-7 (0 hom.)
• Consequence: XYLT2 NM_022167.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.53
• Publications: 0 publications found

Genes affected

XYLT2 (HGNC:15517): (xylosyltransferase 2) The protein encoded by this gene is an isoform of xylosyltransferase, which belongs to a family of glycosyltransferases. This enzyme transfers xylose from UDP-xylose to specific serine residues of the core protein and initiates the biosynthesis of glycosaminoglycan chains in proteoglycans including chondroitin sulfate, heparan sulfate, heparin and dermatan sulfate. The enzyme activity, which is increased in scleroderma patients, is a diagnostic marker for the determination of sclerotic activity in systemic sclerosis. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Dec 2013]

XYLT2 Gene-Disease associations (from GenCC):

• spondylo-ocular syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, BayesDel_addAF, BayesDel_noAF, FATHMM_MKL, M_CAP, PrimateAI, PROVEAN [when max_spliceai, Eigen, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.40646464).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022167.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XYLT2	NM_022167.4	MANE Select	c.8C>A	p.Ala3Glu	missense	Exon 1 of 11	NP_071450.2	Q9H1B5-1
	XYLT2	NR_110010.2		n.23C>A		non_coding_transcript_exon	Exon 1 of 10

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XYLT2	ENST00000017003.7	TSL:1 MANE Select	c.8C>A	p.Ala3Glu	missense	Exon 1 of 11	ENSP00000017003.2	Q9H1B5-1
	XYLT2	ENST00000376550.7	TSL:1	n.8C>A		non_coding_transcript_exon	Exon 1 of 10	ENSP00000365733.3	A0A0C4DFW8
	XYLT2	ENST00000854775.1		c.8C>A	p.Ala3Glu	missense	Exon 1 of 11	ENSP00000524834.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00 AC: 0 AN: 76686 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 9.01e-7 AC: 1 AN: 1109508 Hom.: 0 Cov.: 30 AF XY: 0.00000183 AC XY: 1 AN XY: 545702

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

African (AFR) AF: 0.00 AC: 0 AN: 21440

American (AMR) AF: 0.00 AC: 0 AN: 18562

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15580

East Asian (EAS) AF: 0.00 AC: 0 AN: 15938

South Asian (SAS) AF: 0.00 AC: 0 AN: 58962

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 26234

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2848

European-Non Finnish (NFE) AF: 0.00000110 AC: 1 AN: 909974

Other (OTH) AF: 0.00 AC: 0 AN: 39970

⚠️ 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.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.33
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.077	T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.14
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.84	T
M_CAP	Pathogenic	0.62	D
MetaRNN	Benign	0.41	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		4.5
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.29
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.019	D
Polyphen		0.012	B
Vest4		0.63
MutPred		0.29		Gain of solvent accessibility (P = 0.0145)
MVP		0.24
MPC		0.49
ClinPred		0.97	D
GERP RS		3.2
PromoterAI		-0.36	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.62
gMVP		0.73
Mutation Taster		=51/49	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1186744711; hg19: chr17-48423509;