dbSNP rs397514546: RXYLT1:p.Gly94GlufsTer33 (chr12-63781125-GA-G) – ACMG Classification: Pathogenic (11 pts)

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1PM2PP5

The NM_014254.3(RXYLT1):c.279delA(p.Gly94GlufsTer33) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,455,088 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. K93K) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

RXYLT1
NM_014254.3 frameshift

Scores

Not classified

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 0.959

Publications

1 publications found

Variant links:

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]

RXYLT1 Gene-Disease associations (from GenCC):

muscle-eye-brain disease
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type a, 10
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp
muscular dystrophy-dystroglycanopathy, type A
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

RXYLT1 links:

ENSG00000249753 (HGNC:):

ENSG00000249753 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 11 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 12-63781125-GA-G is Pathogenic according to our data. Variant chr12-63781125-GA-G is described in ClinVar as Pathogenic. ClinVar VariationId is 39607.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RXYLT1	NM_014254.3 link	c.279delA	p.Gly94GlufsTer33	frameshift_variant	Exon 2 of 6	ENST00000261234.11	NP_055069.1	Q9Y2B1
RXYLT1	XM_047428079.1 link	c.279delA	p.Gly94GlufsTer33	frameshift_variant	Exon 2 of 5		XP_047284035.1
RXYLT1	NM_001278237.2 link	c.-502delA		5_prime_UTR_variant	Exon 2 of 6		NP_001265166.1	Q9Y2B1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RXYLT1	ENST00000261234.11 link	c.279delA	p.Gly94GlufsTer33	frameshift_variant	Exon 2 of 6	1	NM_014254.3	ENSP00000261234.6		Q9Y2B1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000407

AC:

AN:

245692

AF XY:

0.00000752

show subpopulations

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:

0.000168

GnomAD4 exome

AF:

6.87e-7

AC:

AN:

1455088

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

723804

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33128

American (AMR)

AF:

0.00

AC:

AN:

43392

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26010

East Asian (EAS)

AF:

0.00

AC:

AN:

39176

South Asian (SAS)

AF:

0.00

AC:

AN:

84824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53296

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5738

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1109430

Other (OTH)

AF:

0.00

AC:

AN:

60094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

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

Pathogenic:1

Dec 07, 2012

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

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Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.96

Mutation Taster

=12/188

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over