rs73122634

chr12-63781124-C-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.275C>T(p.Thr92Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00433 in 1,606,588 control chromosomes in the GnomAD database, including 25 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0042 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0043 (24 hom.)
• Consequence: RXYLT1 NM_014254.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.53

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0034768581).
• BP6: Variant 12-63781124-C-T is Benign according to our data. Variant chr12-63781124-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 260375.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00417 (635/152140) while in subpopulation AMR AF= 0.00537 (82/15284). AF 95% confidence interval is 0.00443. There are 1 homozygotes in gnomad4. There are 331 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RXYLT1	NM_014254.3	c.275C>T	p.Thr92Met	missense_variant	2/6	ENST00000261234.11
RXYLT1	XM_047428079.1	c.275C>T	p.Thr92Met	missense_variant	2/5
RXYLT1	NM_001278237.2	c.-506C>T		5_prime_UTR_variant	2/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RXYLT1	ENST00000261234.11	c.275C>T	p.Thr92Met	missense_variant	2/6	1	NM_014254.3	P1
	ENST00000509615.2	n.238+14357G>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.00418 AC: 635 AN: 152022 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000652

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00537

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0185

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00478

Gnomad OTH AF: 0.00240

GnomAD3 exomes AF: 0.00471 AC: 1155 AN: 245374 Hom.: 7 AF XY: 0.00461 AC XY: 612 AN XY: 132854

Gnomad AFR exome AF: 0.000566

Gnomad AMR exome AF: 0.00345

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000204

Gnomad FIN exome AF: 0.0178

Gnomad NFE exome AF: 0.00553

Gnomad OTH exome AF: 0.00404

GnomAD4 exome AF: 0.00434 AC: 6316 AN: 1454448 Hom.: 24 Cov.: 30 AF XY: 0.00410 AC XY: 2963 AN XY: 723426

Gnomad4 AFR exome AF: 0.000453

Gnomad4 AMR exome AF: 0.00364

Gnomad4 ASJ exome AF: 0.0000385

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000201

Gnomad4 FIN exome AF: 0.0186

Gnomad4 NFE exome AF: 0.00443

Gnomad4 OTH exome AF: 0.00368

GnomAD4 genome AF: 0.00417 AC: 635 AN: 152140 Hom.: 1 Cov.: 33 AF XY: 0.00445 AC XY: 331 AN XY: 74374

Gnomad4 AFR AF: 0.000650

Gnomad4 AMR AF: 0.00537

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0185

Gnomad4 NFE AF: 0.00478

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00357 Hom.: 3

Bravo AF: 0.00283

TwinsUK AF: 0.00431 AC: 16

ALSPAC AF: 0.00701 AC: 27

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00465 AC: 40

ExAC AF: 0.00470 AC: 570

Asia WGS AF: 0.000578 AC: 2 AN: 3474

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Nov 18, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	RXYLT1: BP4, BS2 -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 20, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.54
Cadd	Benign	18
Dann	Benign	0.95
DEOGEN2	Benign	0.0029	T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.72	T
MetaRNN	Benign	0.0035	T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.029
Sift	Benign	0.066	T
Sift4G	Benign	0.098	T
Polyphen		0.013	B
Vest4		0.15
MVP		0.048
MPC		0.18
ClinPred		0.013	T
GERP RS		2.3
Varity_R		0.039
gMVP		0.21

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: rs73122634; hg19: chr12-64174904;