rs141536395

chr12-63808986-A-G

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.1226A>G(p.Glu409Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00104 in 1,612,494 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0060 (9 hom., cov: 32)
  • Exomes 𝑓: 0.00053 (9 hom.)
• Consequence: RXYLT1 NM_014254.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 7.28

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

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005658388).
• BP6: Variant 12-63808986-A-G is Benign according to our data. Variant chr12-63808986-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 260374.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 = 0.00603 (918/152364) while in subpopulation AFR AF= 0.0211 (879/41580). AF 95% confidence interval is 0.02. There are 9 homozygotes in gnomad4. There are 475 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RXYLT1	NM_014254.3	c.1226A>G	p.Glu409Gly	missense_variant	6/6	ENST00000261234.11
RXYLT1-AS1	NR_126167.1	n.468-46T>C		intron_variant, non_coding_transcript_variant
RXYLT1	NM_001278237.2	c.446A>G	p.Glu149Gly	missense_variant	6/6
RXYLT1	XM_047428078.1	c.917A>G	p.Glu306Gly	missense_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RXYLT1	ENST00000261234.11	c.1226A>G	p.Glu409Gly	missense_variant	6/6	1	NM_014254.3	P1
RXYLT1-AS1	ENST00000546214.1	n.468-46T>C		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.00603 AC: 918 AN: 152246 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.0212

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00183

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00140 AC: 348 AN: 248824 Hom.: 4 AF XY: 0.00104 AC XY: 141 AN XY: 135064

Gnomad AFR exome AF: 0.0201

Gnomad AMR exome AF: 0.000932

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: 0.00000888

Gnomad OTH exome AF: 0.000663

GnomAD4 exome AF: 0.000525 AC: 767 AN: 1460130 Hom.: 9 Cov.: 30 AF XY: 0.000434 AC XY: 315 AN XY: 726418

Gnomad4 AFR exome AF: 0.0194

Gnomad4 AMR exome AF: 0.00126

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000466

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.000879

GnomAD4 genome AF: 0.00603 AC: 918 AN: 152364 Hom.: 9 Cov.: 32 AF XY: 0.00638 AC XY: 475 AN XY: 74506

Gnomad4 AFR AF: 0.0211

Gnomad4 AMR AF: 0.00183

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.000549 Hom.: 3

Bravo AF: 0.00716

ESP6500AA AF: 0.0164 AC: 72

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00186 AC: 226

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 02, 2017	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	-	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type a, 10 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 20, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.44
Cadd	Uncertain	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.10	T;.
Eigen	Benign	-0.034
Eigen_PC	Benign	0.16
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.78	T;T
MetaRNN	Benign	0.0057	T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.26	T
PROVEAN	Uncertain	-3.2	D;D
REVEL	Benign	0.091
Sift	Benign	0.15	T;T
Sift4G	Benign	0.24	T;T
Polyphen		0.066	B;B
Vest4		0.15
MVP		0.10
MPC		0.21
ClinPred		0.030	T
GERP RS		5.0
Varity_R		0.14
gMVP		0.42

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: rs141536395; hg19: chr12-64202766;