12-63802131-G-A

Variant names:

• chr12-63802131-G-A
• rs114036100
• NM_014254.3:c.469G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_014254.3(RXYLT1):​c.469G>A​(p.Val157Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00197 in 1,612,092 control chromosomes in the GnomAD database, including 42 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (21 hom., cov: 31)
  • Exomes 𝑓: 0.0011 (21 hom.)
• Consequence: RXYLT1 NM_014254.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.133
• Publications: 5 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0022054315).
• BP6: Variant 12-63802131-G-A is Benign according to our data. Variant chr12-63802131-G-A is described in ClinVar as Benign. ClinVar VariationId is 130596.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0105 (1594/152222) while in subpopulation AFR AF = 0.0363 (1508/41528). AF 95% confidence interval is 0.0348. There are 21 homozygotes in GnomAd4. There are 764 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 21 AR gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RXYLT1	NM_014254.3	MANE Select	c.469G>A	p.Val157Ile	missense	Exon 4 of 6	NP_055069.1
	RXYLT1	NM_001278237.2		c.-312G>A		5_prime_UTR	Exon 4 of 6	NP_001265166.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RXYLT1	ENST00000261234.11	TSL:1 MANE Select	c.469G>A	p.Val157Ile	missense	Exon 4 of 6	ENSP00000261234.6
	RXYLT1	ENST00000537373.6	TSL:1	n.*204G>A		non_coding_transcript_exon	Exon 4 of 6	ENSP00000440280.2
	RXYLT1	ENST00000537373.6	TSL:1	n.*204G>A		3_prime_UTR	Exon 4 of 6	ENSP00000440280.2

Frequencies

GnomAD3 genomes AF: 0.0105 AC: 1591 AN: 152104 Hom.: 21 Cov.: 31

Gnomad AFR AF: 0.0363

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00373

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00267 AC: 667 AN: 249602 AF XY: 0.00206

Gnomad AFR exome AF: 0.0357

Gnomad AMR exome AF: 0.00152

Gnomad ASJ exome AF: 0.000100

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000195

Gnomad OTH exome AF: 0.00165

GnomAD4 exome AF: 0.00108 AC: 1576 AN: 1459870 Hom.: 21 Cov.: 31 AF XY: 0.000959 AC XY: 696 AN XY: 726042

African (AFR) AF: 0.0358 AC: 1194 AN: 33344

American (AMR) AF: 0.00200 AC: 89 AN: 44420

Ashkenazi Jewish (ASJ) AF: 0.0000384 AC: 1 AN: 26036

East Asian (EAS) AF: 0.0000757 AC: 3 AN: 39644

South Asian (SAS) AF: 0.000151 AC: 13 AN: 85852

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53382

Middle Eastern (MID) AF: 0.00278 AC: 16 AN: 5750

European-Non Finnish (NFE) AF: 0.000116 AC: 129 AN: 1111142

Other (OTH) AF: 0.00217 AC: 131 AN: 60300

GnomAD4 genome AF: 0.0105 AC: 1594 AN: 152222 Hom.: 21 Cov.: 31 AF XY: 0.0103 AC XY: 764 AN XY: 74424

African (AFR) AF: 0.0363 AC: 1508 AN: 41528

American (AMR) AF: 0.00373 AC: 57 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10588

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000265 AC: 18 AN: 68024

Other (OTH) AF: 0.00473 AC: 10 AN: 2114

Alfa AF: 0.00339 Hom.: 16

Bravo AF: 0.0120

ESP6500AA AF: 0.0390 AC: 172

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00343 AC: 416

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000601

EpiControl AF: 0.000474

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Jan 13, 2020

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed.

Jun 16, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	0.099
DANN	Benign	0.42
DEOGEN2	Benign	0.0044	T
Eigen	Benign	-0.94
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.082	N
LIST_S2	Benign	0.67	T
MetaRNN	Benign	0.0022	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.13
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.47	N
REVEL	Benign	0.034
Sift	Benign	0.55	T
Sift4G	Benign	0.23	T
Polyphen		0.0070	B
Vest4		0.077
MVP		0.014
MPC		0.13
ClinPred		0.00051	T
GERP RS		-0.052
Varity_R		0.0086
gMVP		0.18
Mutation Taster		=299/1	polymorphism

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

Other links and lift over

dbSNP: rs114036100; hg19: chr12-64195911;