rs114036100

Positions:

• chr12-63802131-G-A
• chr12-63802131-G-T

Variant summary

Our verdict is Benign. Variant got -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. 13/19 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

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 id 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 male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 21 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RXYLT1	NM_014254.3	c.469G>A	p.Val157Ile	missense_variant	4/6	ENST00000261234.11	NP_055069.1
RXYLT1	XM_047428078.1	c.160G>A	p.Val54Ile	missense_variant	3/5		XP_047284034.1
RXYLT1	NM_001278237.2	c.-312G>A		5_prime_UTR_variant	4/6		NP_001265166.1
RXYLT1	XM_047428079.1	c.*18G>A		3_prime_UTR_variant	5/5		XP_047284035.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RXYLT1	ENST00000261234.11	c.469G>A	p.Val157Ile	missense_variant	4/6	1	NM_014254.3	ENSP00000261234.6

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

GnomAD3 exomes AF: 0.00267 AC: 667 AN: 249602 Hom.: 7 AF XY: 0.00206 AC XY: 278 AN XY: 134850

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 SAS exome AF: 0.0000331

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

Gnomad4 AFR exome AF: 0.0358

Gnomad4 AMR exome AF: 0.00200

Gnomad4 ASJ exome AF: 0.0000384

Gnomad4 EAS exome AF: 0.0000757

Gnomad4 SAS exome AF: 0.000151

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000116

Gnomad4 OTH exome AF: 0.00217

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

Gnomad4 AFR AF: 0.0363

Gnomad4 AMR AF: 0.00373

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00155 Hom.: 3

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

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 16, 2016	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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	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. -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 13, 2020	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Computational scores

Source: dbNSFP v4.3

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
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

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

LitVar

Other links and lift over

dbSNP: rs114036100; hg19: chr12-64195911;