NM_014254.3:c.743+1G>A

Variant names:

• chr12-63802406-G-A
• rs778174763
• NM_014254.3:c.743+1G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_014254.3(RXYLT1):​c.743+1G>A variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000426 in 1,406,972 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000043 (0 hom.)
• Consequence: RXYLT1 NM_014254.3 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.31
• Publications: 2 publications found

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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.23648648 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-63802406-G-A is Pathogenic according to our data. Variant chr12-63802406-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 578816.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RXYLT1	NM_014254.3	c.743+1G>A		splice_donor_variant, intron_variant	Intron 4 of 5	ENST00000261234.11	NP_055069.1
RXYLT1	NM_001278237.2	c.-38+1G>A		splice_donor_variant, intron_variant	Intron 4 of 5		NP_001265166.1
RXYLT1	XM_047428078.1	c.434+1G>A		splice_donor_variant, intron_variant	Intron 3 of 4		XP_047284034.1
RXYLT1	XM_047428079.1	c.*293G>A		downstream_gene_variant			XP_047284035.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RXYLT1	ENST00000261234.11	c.743+1G>A		splice_donor_variant, intron_variant	Intron 4 of 5	1	NM_014254.3	ENSP00000261234.6

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000924 AC: 2 AN: 216442 AF XY: 0.00000854

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: 0.0000194

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000426 AC: 6 AN: 1406972 Hom.: 0 Cov.: 31 AF XY: 0.00000432 AC XY: 3 AN XY: 693710

African (AFR) AF: 0.00 AC: 0 AN: 30978

American (AMR) AF: 0.00 AC: 0 AN: 35122

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23826

East Asian (EAS) AF: 0.00 AC: 0 AN: 38868

South Asian (SAS) AF: 0.0000127 AC: 1 AN: 78506

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52184

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5522

European-Non Finnish (NFE) AF: 0.00000369 AC: 4 AN: 1084126

Other (OTH) AF: 0.0000173 AC: 1 AN: 57840

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Nov 27, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects a donor splice site in intron 4 of the RXYLT1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in RXYLT1 are known to be pathogenic (PMID: 23217329, 23519211, 31742715). This variant is present in population databases (rs778174763, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with RXYLT1-related conditions. ClinVar contains an entry for this variant (Variation ID: 578816). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.61	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	33
DANN	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	0.99
FATHMM_MKL	Uncertain	0.96	D
PhyloP100		9.3
GERP RS		4.9
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.99		Position offset: -1

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

Other links and lift over

dbSNP: rs778174763; hg19: chr12-64196186; COSMIC: COSV54170575; COSMIC: COSV54170575;