rs397514696

Variant names:

• chr12-63780094-AG-A
• rs397514696
• NM_014254.3:c.139delG

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_014254.3(RXYLT1):​c.139delG​(p.Ala47ArgfsTer42) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000106 in 1,415,992 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: RXYLT1 NM_014254.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 0.0240

Genes affected

RXYLT1 (HGNC:13530): (ribitol xylosyltransferase 1) This gene encodes a type II transmembrane protein that is thought to have glycosyltransferase function. Mutations in this gene result in cobblestone lissencephaly. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, May 2013]

ENSG00000249753 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-63780094-AG-A is Pathogenic according to our data. Variant chr12-63780094-AG-A is described in ClinVar as [Pathogenic]. Clinvar id is 50607.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-63780094-AG-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RXYLT1	NM_014254.3	c.139delG	p.Ala47ArgfsTer42	frameshift_variant	Exon 1 of 6	ENST00000261234.11	NP_055069.1
RXYLT1	XM_047428079.1	c.139delG	p.Ala47ArgfsTer42	frameshift_variant	Exon 1 of 5		XP_047284035.1
RXYLT1	NM_001278237.2	c.-975delG		5_prime_UTR_variant	Exon 1 of 6		NP_001265166.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RXYLT1	ENST00000261234.11	c.139delG	p.Ala47ArgfsTer42	frameshift_variant	Exon 1 of 6	1	NM_014254.3	ENSP00000261234.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000106 AC: 15 AN: 1415992 Hom.: 0 Cov.: 31 AF XY: 0.0000128 AC XY: 9 AN XY: 701908

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: 0.0000602

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000823

Gnomad4 OTH exome AF: 0.0000170

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000113

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Nov 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Ala47Argfs*42) in the RXYLT1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RXYLT1 are known to be pathogenic (PMID: 23217329, 23519211, 31742715). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with clinical features of muscular dystrophy-dystroglycanopathy (PMID: 23519211, 34490615). ClinVar contains an entry for this variant (Variation ID: 50607). For these reasons, this variant has been classified as Pathogenic. -

Apr 01, 2020

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type a, 10 Pathogenic:1

Apr 26, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

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: rs397514696; hg19: chr12-64173874;