rs778174763

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr12-63802406-G-A
• chr12-63802406-G-C
• chr12-63802406-G-T

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: PanelApp Australia, Genomics England PanelApp, G2P
• 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 VariationId is 578816.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014254.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RXYLT1	NM_014254.3	MANE Select	c.743+1G>A		splice_donor intron	N/A	NP_055069.1	Q9Y2B1
	RXYLT1	NM_001278237.2		c.-38+1G>A		splice_donor intron	N/A	NP_001265166.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RXYLT1	ENST00000261234.11	TSL:1 MANE Select	c.743+1G>A		splice_donor intron	N/A	ENSP00000261234.6	Q9Y2B1
	RXYLT1	ENST00000537373.6	TSL:1	n.*478+1G>A		splice_donor intron	N/A	ENSP00000440280.2	G3V1K2
	RXYLT1	ENST00000947510.1		c.743+1G>A		splice_donor intron	N/A	ENSP00000617569.1

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

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

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;