3-141292303-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001037172.3(PXYLP1):c.541A>T(p.Arg181Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PXYLP1 NM_001037172.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.36

Genes affected

PXYLP1 (HGNC:26303): (2-phosphoxylose phosphatase 1) Enables phosphatase activity. Involved in chondroitin sulfate proteoglycan biosynthetic process; glycosaminoglycan biosynthetic process; and positive regulation of heparan sulfate proteoglycan biosynthetic process. Located in Golgi apparatus. [provided by Alliance of Genome Resources, Apr 2022]

(HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.972

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PXYLP1	NM_001037172.3	c.541A>T	p.Arg181Trp	missense_variant	6/6	ENST00000286353.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PXYLP1	ENST00000286353.9	c.541A>T	p.Arg181Trp	missense_variant	6/6	1	NM_001037172.3	P1
	ENST00000507698.1	n.167-24695T>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 20, 2023

The c.541A>T (p.R181W) alteration is located in exon 8 (coding exon 5) of the PXYLP1 gene. This alteration results from a A to T substitution at nucleotide position 541, causing the arginine (R) at amino acid position 181 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.14	T;T;T;T;.
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.84	D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D
MetaSVM	Uncertain	0.19	D
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-4.8	D;D;D;D;D
REVEL	Pathogenic	0.74
Sift	Uncertain	0.0010	D;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D
Polyphen		1.0	D;.;D;D;.
Vest4		0.62
MutPred		0.91		Loss of stability (P = 0.1793);.;Loss of stability (P = 0.1793);.;.;
MVP		0.55
MPC		0.85
ClinPred		1.0	D
GERP RS		-0.41
Varity_R		0.52
gMVP		0.80

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-141011145;