NM_014254.3:c.1226A>G

Variant names:

• chr12-63808986-A-G
• rs141536395
• NM_014254.3:c.1226A>G

Variant summary

Our verdict is Benign. The variant received -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:5
• Conservation: PhyloP100: 7.28
• Publications: 2 publications found

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

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 9 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014254.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RXYLT1	NM_014254.3	MANE Select	c.1226A>G	p.Glu409Gly	missense	Exon 6 of 6	NP_055069.1	Q9Y2B1
	RXYLT1	NM_001278237.2		c.446A>G	p.Glu149Gly	missense	Exon 6 of 6	NP_001265166.1
	RXYLT1-AS1	NR_126167.1		n.468-46T>C		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RXYLT1	ENST00000261234.11	TSL:1 MANE Select	c.1226A>G	p.Glu409Gly	missense	Exon 6 of 6	ENSP00000261234.6	Q9Y2B1
	RXYLT1	ENST00000537373.6	TSL:1	n.*961A>G		non_coding_transcript_exon	Exon 6 of 6	ENSP00000440280.2	G3V1K2
	RXYLT1	ENST00000537373.6	TSL:1	n.*961A>G		3_prime_UTR	Exon 6 of 6	ENSP00000440280.2	G3V1K2

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

GnomAD2 exomes AF: 0.00140 AC: 348 AN: 248824 AF XY: 0.00104

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 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

African (AFR) AF: 0.0194 AC: 646 AN: 33294

American (AMR) AF: 0.00126 AC: 56 AN: 44452

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.0000466 AC: 4 AN: 85834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53386

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5764

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111276

Other (OTH) AF: 0.000879 AC: 53 AN: 60314

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

African (AFR) AF: 0.0211 AC: 879 AN: 41580

American (AMR) AF: 0.00183 AC: 28 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68044

Other (OTH) AF: 0.00473 AC: 10 AN: 2114

Alfa AF: 0.00198 Hom.: 7

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

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type a, 10 (1)

Computational scores

Source: dbNSFP v4.9

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
MetaRNN	Benign	0.0057	T
MetaSVM	Benign	-1.1	T
PhyloP100		7.3
PrimateAI	Benign	0.26	T
PROVEAN	Uncertain	-3.2	D
REVEL	Benign	0.091
Sift	Benign	0.15	T
Sift4G	Benign	0.24	T
Polyphen		0.066	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
Mutation Taster		=90/10	polymorphism

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

Other links and lift over

dbSNP: rs141536395; hg19: chr12-64202766; COSMIC: COSV107198717; COSMIC: COSV107198717;