chr12-63780027-G-A

Position:

• chr12-63780027-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_014254.3(RXYLT1):​c.67G>A​(p.Ala23Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0968 in 1,609,046 control chromosomes in the GnomAD database, including 8,262 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.076 (589 hom., cov: 32)
  • Exomes 𝑓: 0.099 (7673 hom.)
• Consequence: RXYLT1 NM_014254.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 5.05

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=0.0017903745).
• BP6: Variant 12-63780027-G-A is Benign according to our data. Variant chr12-63780027-G-A is described in ClinVar as [Benign]. Clinvar id is 130597.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-63780027-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.107 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RXYLT1	NM_014254.3	c.67G>A	p.Ala23Thr	missense_variant	1/6	ENST00000261234.11	NP_055069.1
RXYLT1	XM_047428079.1	c.67G>A	p.Ala23Thr	missense_variant	1/5		XP_047284035.1
RXYLT1	NM_001278237.2	c.-1047G>A		5_prime_UTR_variant	1/6		NP_001265166.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RXYLT1	ENST00000261234.11	c.67G>A	p.Ala23Thr	missense_variant	1/6	1	NM_014254.3	ENSP00000261234	P1
	ENST00000509615.2	n.238+15454C>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.0765 AC: 11628 AN: 152028 Hom.: 590 Cov.: 32

Gnomad AFR AF: 0.0244

Gnomad AMI AF: 0.113

Gnomad AMR AF: 0.0512

Gnomad ASJ AF: 0.0793

Gnomad EAS AF: 0.0112

Gnomad SAS AF: 0.105

Gnomad FIN AF: 0.122

Gnomad MID AF: 0.179

Gnomad NFE AF: 0.109

Gnomad OTH AF: 0.0757

GnomAD3 exomes AF: 0.0866 AC: 21260 AN: 245612 Hom.: 1135 AF XY: 0.0912 AC XY: 12157 AN XY: 133354

Gnomad AFR exome AF: 0.0242

Gnomad AMR exome AF: 0.0418

Gnomad ASJ exome AF: 0.0828

Gnomad EAS exome AF: 0.0120

Gnomad SAS exome AF: 0.107

Gnomad FIN exome AF: 0.115

Gnomad NFE exome AF: 0.110

Gnomad OTH exome AF: 0.0982

GnomAD4 exome AF: 0.0989 AC: 144161 AN: 1456910 Hom.: 7673 Cov.: 32 AF XY: 0.100 AC XY: 72657 AN XY: 725056

Gnomad4 AFR exome AF: 0.0235

Gnomad4 AMR exome AF: 0.0446

Gnomad4 ASJ exome AF: 0.0855

Gnomad4 EAS exome AF: 0.0104

Gnomad4 SAS exome AF: 0.106

Gnomad4 FIN exome AF: 0.122

Gnomad4 NFE exome AF: 0.105

Gnomad4 OTH exome AF: 0.0936

GnomAD4 genome AF: 0.0764 AC: 11626 AN: 152136 Hom.: 589 Cov.: 32 AF XY: 0.0766 AC XY: 5694 AN XY: 74370

Gnomad4 AFR AF: 0.0244

Gnomad4 AMR AF: 0.0511

Gnomad4 ASJ AF: 0.0793

Gnomad4 EAS AF: 0.0115

Gnomad4 SAS AF: 0.105

Gnomad4 FIN AF: 0.122

Gnomad4 NFE AF: 0.109

Gnomad4 OTH AF: 0.0758

Alfa AF: 0.0992 Hom.: 1256

Bravo AF: 0.0672

TwinsUK AF: 0.0955 AC: 354

ALSPAC AF: 0.0989 AC: 381

ESP6500AA AF: 0.0284 AC: 125

ESP6500EA AF: 0.105 AC: 903

ExAC AF: 0.0883 AC: 10721

Asia WGS AF: 0.0550 AC: 190 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 30, 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	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -

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	Feb 01, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.48
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0048	T
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Benign	0.70	D
LIST_S2	Uncertain	0.91	D
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-1.2	T
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.43	N
REVEL	Benign	0.089
Sift	Benign	0.28	T
Sift4G	Benign	0.49	T
Polyphen		1.0	D
Vest4		0.22
MPC		2.3
ClinPred		0.023	T
GERP RS		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.092
gMVP		0.70

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: rs61935924; hg19: chr12-64173807; COSMIC: COSV54170288; COSMIC: COSV54170288;