rs1555225967

Positions:

• chr12-63781095-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014254.3(RXYLT1):​c.246A>C​(p.Lys82Asn) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: RXYLT1 NM_014254.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.53

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=0.14218637).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RXYLT1	NM_014254.3	c.246A>C	p.Lys82Asn	missense_variant	2/6	ENST00000261234.11	NP_055069.1
RXYLT1	XM_047428079.1	c.246A>C	p.Lys82Asn	missense_variant	2/5		XP_047284035.1
RXYLT1	NM_001278237.2	c.-535A>C		5_prime_UTR_variant	2/6		NP_001265166.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RXYLT1	ENST00000261234.11	c.246A>C	p.Lys82Asn	missense_variant	2/6	1	NM_014254.3	ENSP00000261234	P1
	ENST00000509615.2	n.238+14386T>G		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 04, 2022

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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 473415). This variant has not been reported in the literature in individuals affected with TMEM5-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 82 of the TMEM5 protein (p.Lys82Asn). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0028	T
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.15
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.85	D;D
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.81	N
REVEL	Benign	0.049
Sift	Benign	0.036	D
Sift4G	Benign	0.40	T
Polyphen		0.36	B
Vest4		0.33
MutPred		0.36		Loss of ubiquitination at K82 (P = 0.003);
MVP		0.092
MPC		0.62
ClinPred		0.76	D
GERP RS		3.1
Varity_R		0.12
gMVP		0.31

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: rs1555225967; hg19: chr12-64174875;