12-63805410-T-G

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3PP5

The NM_014254.3(RXYLT1):c.914+6T>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000699 in 1,574,158 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000063 ( 0 hom. )

Consequence

RXYLT1
NM_014254.3 splice_region, intron

Scores

Splicing: ADA: 0.9971

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:3

Conservation

PhyloP100: 3.46

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 links:

RXYLT1-AS1 (HGNC:48910): (RXYLT1 antisense RNA 1)

RXYLT1-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 12-63805410-T-G is Pathogenic according to our data. Variant chr12-63805410-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 429848.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=3}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
RXYLT1	NM_014254.3 link	c.914+6T>G	splice_region_variant, intron_variant	Intron 5 of 5	ENST00000261234.11	NP_055069.1	Q9Y2B1
RXYLT1	NM_001278237.2 link	c.134+6T>G	splice_region_variant, intron_variant	Intron 5 of 5		NP_001265166.1	Q9Y2B1
RXYLT1	XM_047428078.1 link	c.605+6T>G	splice_region_variant, intron_variant	Intron 4 of 4		XP_047284034.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RXYLT1	ENST00000261234.11 link	c.914+6T>G		splice_region_variant, intron_variant	Intron 5 of 5	1	NM_014254.3	ENSP00000261234.6		Q9Y2B1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152126

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.00000916

AC:

AN:

218386

Hom.:

AF XY:

0.0000169

AC XY:

AN XY:

118326

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 SAS 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:

0.00000633

AC:

AN:

1422032

Hom.:

Cov.:

AF XY:

0.00000567

AC XY:

AN XY:

705662

show subpopulations

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000547

Gnomad4 OTH exome

AF:

0.0000513

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152126

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74314

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000479

Alfa

AF:

0.0000368

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:1

Nov 17, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change falls in intron 5 of the RXYLT1 gene. It does not directly change the encoded amino acid sequence of the RXYLT1 protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs748809209, gnomAD 0.002%). This variant has been observed in individual(s) with clinical features of congenital muscular dystrophy (PMID: 30017359). ClinVar contains an entry for this variant (Variation ID: 429848). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 5, but is expected to preserve the integrity of the reading-frame (PMID: 30017359). 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. -

May 12, 2017

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A variant of uncertain significance has been identified in the TMEM5 gene. The c.914+6 T>G variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The c.914+6 T>G variant not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Several in-silico splice prediction models predict that c.914+6 T>G reduces the natural splice donor site and may and lead to abnormal gene splicing. However, in the absence of RNA/functional studies, the actual effect of this sequence change in this individual is unknown. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -

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

Pathogenic:1Uncertain:1

Jun 30, 2022

Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 12, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: RXYLT1 c.914+6T>G alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant weakens a 5' donor site. One predicts the variant creates a 5' donor site. One predicts the variant no significant impact on splicing. At least one publication reports experimental evidence that this variant affects mRNA splicing result in an in frame skipping of exon 5 in patient samples (example, Zaum_2018). The variant allele was found at a frequency of 7e-06 in 1574158 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in RXYLT1 causing Muscular Dystrophy-Dystroglycanopathy (congenital With Brain And Eye Anomalies), Type A, 10. c.914+6T>G has been reported in the homozygous state in the literature in multiple individuals affected with clinical features of Muscular Dystrophy-Dystroglycanopathy (congenital With Brain And Eye Anomalies), Type A, 10 (example, Al-Kasbi_2022, Zaum_2018), including at least 1 family where it segregated with disease. These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 36344539, 30017359). ClinVar contains an entry for this variant (Variation ID: 429848). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Inborn genetic diseases

Uncertain:1

Jun 24, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.914+6T>G intronic alteration consists of a T to G substitution nucleotides after coding exon 5 in the TMEM5 gene. 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

BayesDel_noAF

Benign

-0.32

CADD

Benign

DANN

Benign

0.92

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.83

SpliceAI score (max)

0.58

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.29

Position offset: -1

DS_DL_spliceai

0.58

Position offset: -6

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over