NM_022167.4:c.8C>A

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 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.

• 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

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 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).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
XYLT2	NM_022167.4	c.8C>A	p.Ala3Glu	missense_variant	Exon 1 of 11	ENST00000017003.7	NP_071450.2
XYLT2	NR_110010.2	n.23C>A		non_coding_transcript_exon_variant	Exon 1 of 10
XYLT2	XM_005257572.5	c.-748C>A		upstream_gene_variant			XP_005257629.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
XYLT2	ENST00000017003.7	c.8C>A	p.Ala3Glu	missense_variant	Exon 1 of 11	1	NM_022167.4	ENSP00000017003.2
XYLT2	ENST00000376550.7	n.8C>A		non_coding_transcript_exon_variant	Exon 1 of 10	1		ENSP00000365733.3
XYLT2	ENST00000507602.5	c.8C>A	p.Ala3Glu	missense_variant	Exon 1 of 10	2		ENSP00000426501.1
XYLT2	ENST00000509778.1	c.8C>A	p.Ala3Glu	missense_variant	Exon 1 of 2	3		ENSP00000425511.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 9.01e-7 AC: 1 AN: 1109508 Hom.: 0 Cov.: 30 AF XY: 0.00000183 AC XY: 1 AN XY: 545702

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000110

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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;T;T
M_CAP	Pathogenic	0.62	D
MetaRNN	Benign	0.41	T;T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Uncertain	2.2	M;.;.
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	-1.1	N;D;N
REVEL	Uncertain	0.29
Sift	Uncertain	0.0060	D;D;D
Sift4G	Uncertain	0.019	D;D;D
Polyphen		0.012	B;.;.
Vest4		0.63
MutPred		0.29		Gain of solvent accessibility (P = 0.0145);Gain of solvent accessibility (P = 0.0145);Gain of solvent accessibility (P = 0.0145);
MVP		0.24
MPC		0.49
ClinPred		0.97	D
GERP RS		3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.62
gMVP		0.73

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

Publications

LitVar

Other links and lift over

dbSNP: rs1186744711; hg19: chr17-48423509;