12-63779961-A-T

Position:

• chr12-63779961-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_001278237.2(RXYLT1):​c.-1113A>T variant causes a 5 prime UTR premature start codon gain change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RXYLT1 NM_001278237.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.21

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988
• PP5: Variant 12-63779961-A-T is Pathogenic according to our data. Variant chr12-63779961-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3252988.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RXYLT1	NM_014254.3	c.1A>T	p.Met1?	initiator_codon_variant	1/6	ENST00000261234.11	NP_055069.1
RXYLT1	NM_001278237.2	c.-1113A>T		5_prime_UTR_premature_start_codon_gain_variant	1/6		NP_001265166.1
RXYLT1	XM_047428079.1	c.1A>T	p.Met1?	initiator_codon_variant	1/5		XP_047284035.1
RXYLT1	NM_001278237.2	c.-1113A>T		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.1A>T	p.Met1?	initiator_codon_variant	1/6	1	NM_014254.3	ENSP00000261234.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jul 25, 2023

Initiation codon variant in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Uncertain	25
DANN	Benign	0.96
DEOGEN2	Benign	0.075	T
Eigen	Benign	0.18
Eigen_PC	Benign	0.12
FATHMM_MKL	Benign	0.74	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Benign	-0.88	T
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.35
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.80	P
Vest4		0.84
MutPred		0.98		Gain of ubiquitination at K6 (P = 0.0513);
MVP		0.10
ClinPred		1.0	D
GERP RS		3.4
Varity_R		0.93
gMVP		0.62

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-64173741;