rs73122634

Variant names:

• chr12-63781124-C-T
• rs73122634
• NM_014254.3:c.275C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001278237.2(RXYLT1):​c.-506C>T variant causes a 5 prime UTR premature start codon gain 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. 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_001278237.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.53
• Publications: 8 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 Gene-Disease associations (from GenCC):

• muscle-eye-brain disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type a, 10

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp
• muscular dystrophy-dystroglycanopathy, type A

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000249753 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 24 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001278237.2. 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.275C>T	p.Thr92Met	missense	Exon 2 of 6	NP_055069.1
	RXYLT1	NM_001278237.2		c.-506C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 6	NP_001265166.1
	RXYLT1	NM_001278237.2		c.-506C>T		5_prime_UTR	Exon 2 of 6	NP_001265166.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RXYLT1	ENST00000261234.11	TSL:1 MANE Select	c.275C>T	p.Thr92Met	missense	Exon 2 of 6	ENSP00000261234.6
	RXYLT1	ENST00000536219.5	TSL:1	n.394C>T		non_coding_transcript_exon	Exon 2 of 3
	RXYLT1	ENST00000537373.6	TSL:1	n.*10C>T		non_coding_transcript_exon	Exon 2 of 6	ENSP00000440280.2

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

GnomAD2 exomes AF: 0.00471 AC: 1155 AN: 245374 AF XY: 0.00461

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 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

African (AFR) AF: 0.000453 AC: 15 AN: 33078

American (AMR) AF: 0.00364 AC: 158 AN: 43364

Ashkenazi Jewish (ASJ) AF: 0.0000385 AC: 1 AN: 25992

East Asian (EAS) AF: 0.00 AC: 0 AN: 39128

South Asian (SAS) AF: 0.000201 AC: 17 AN: 84710

European-Finnish (FIN) AF: 0.0186 AC: 993 AN: 53278

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5740

European-Non Finnish (NFE) AF: 0.00443 AC: 4911 AN: 1109122

Other (OTH) AF: 0.00368 AC: 221 AN: 60036

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

African (AFR) AF: 0.000650 AC: 27 AN: 41508

American (AMR) AF: 0.00537 AC: 82 AN: 15284

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.0185 AC: 196 AN: 10580

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

European-Non Finnish (NFE) AF: 0.00478 AC: 325 AN: 67968

Other (OTH) AF: 0.00237 AC: 5 AN: 2108

Alfa AF: 0.00374 Hom.: 4

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

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		1.5
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
Mutation Taster		=100/0	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: rs73122634; hg19: chr12-64174904; COSMIC: COSV107198743;