12-63780040-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4 BS1_Supporting

The NM_014254.3(RXYLT1):c.80T>C(p.Val27Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000158 in 1,455,556 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. V27V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: RXYLT1 NM_014254.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.11

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]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31491432).
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.0000158 (23/1455556) while in subpopulation MID AF= 0.00348 (20/5744). AF 95% confidence interval is 0.00231. There are 0 homozygotes in gnomad4_exome. There are 12 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RXYLT1	NM_014254.3	c.80T>C	p.Val27Ala	missense_variant	1/6	ENST00000261234.11
RXYLT1	XM_047428079.1	c.80T>C	p.Val27Ala	missense_variant	1/5
RXYLT1	NM_001278237.2	c.-1034T>C		5_prime_UTR_variant	1/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RXYLT1	ENST00000261234.11	c.80T>C	p.Val27Ala	missense_variant	1/6	1	NM_014254.3	P1
	ENST00000509615.2	n.238+15441A>G		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000575 AC: 14 AN: 243422 Hom.: 0 AF XY: 0.0000604 AC XY: 8 AN XY: 132476

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: 0.0000545

Gnomad OTH exome AF: 0.00135

GnomAD4 exome AF: 0.0000158 AC: 23 AN: 1455556 Hom.: 0 Cov.: 31 AF XY: 0.0000166 AC XY: 12 AN XY: 724400

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: 0.00

Gnomad4 OTH exome AF: 0.0000499

GnomAD4 genome Cov.: 33

Alfa AF: 0.00156 Hom.: 0

ExAC AF: 0.0000412 AC: 5

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Sep 27, 2022	This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 27 of the RXYLT1 protein (p.Val27Ala). This variant is present in population databases (rs779346062, gnomAD 0.005%). This variant has not been reported in the literature in individuals affected with RXYLT1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1188040). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt RXYLT1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 16, 2020	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Benign	-0.074	T
BayesDel_noAF	Benign	-0.21
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.010	T
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.036
FATHMM_MKL	Benign	0.56	D
LIST_S2	Benign	0.74	T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.31	T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.14
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.011	D
Polyphen		0.23	B
Vest4		0.61
MutPred		0.38		Gain of catalytic residue at Y22 (P = 8e-04);
MVP		0.072
MPC		1.8
ClinPred		0.26	T
GERP RS		3.4
Varity_R		0.17
gMVP		0.57

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: rs779346062; hg19: chr12-64173820;