X-48478081-T-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Moderate PP5_Moderate

The NM_012280.4(FTSJ1):c.34T>A(p.Tyr12Asn) variant causes a missense change involving the alteration of a conserved nucleotide. 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 Pathogenic (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: FTSJ1 NM_012280.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.23

Genes affected

FTSJ1 (HGNC:13254): (FtsJ RNA 2'-O-methyltransferase 1) This gene encodes a member of the methyltransferase superfamily. The encoded protein localizes to the nucleolus, binds to S-adenosylmethionine, and may be involved in the processing and modification of ribosomal RNA. Mutations in this gene are associated with cognitive disability. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2013]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.912
• PP5: Variant X-48478081-T-A is Pathogenic according to our data. Variant chrX-48478081-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 208659.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FTSJ1	NM_012280.4	c.34T>A	p.Tyr12Asn	missense_variant	2/13	ENST00000348411.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FTSJ1	ENST00000348411.3	c.34T>A	p.Tyr12Asn	missense_variant	2/13	1	NM_012280.4	P4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 27, 2013

​The c.34T>A (p.Y12N) alteration is located in coding exon 1 of the FTSJ1 gene. This alteration results from a T to A substitution at nucleotide position 34. The tyrosine (Y) at codon 12 is replaced by asparagine (N), an amino acid with dissimilar properties.The missense change is not observed in healthy cohorts:Based on data from the NHLBI Exome Sequencing Project (ESP), the FTSJ1: c.34T>A (p.Y12N) alteration was not observed among 6,503 individuals tested (0.0%). Allele frequency data for this nucleotide position is not currently available from the 1000 Genomes Project and the alteration is not currently listed in the Database of Single Nucleotide Polymorphisms (dbSNP).The altered amino acid is conserved throughout evolution:The p.Y12 amino acid is conserved throughout vertebrates.The alteration is predicted deleterious by in silico models:The p.Y12N alteration is predicted to be probably damaging by Polyphen and deleterious by SIFT in silico analyses.The alteration has been observedde novo:The alteration was detected in our laboratory via exome sequencing in a female patient with phenotypic features overlapping with the established FTSJ1disease association. Co-segregation analysis revealed the absence of the alteration in the patient's mother and father, indicating a likely de novo mutation occurrence. Whether the female patient had skewed X-inactivation was unknown.Based on the available evidence, the FTSJ1: c.34T>A (p.Y12N) alteration is classified as a pathogenic mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.17
Cadd	Pathogenic	29
Dann	Uncertain	0.99
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.41	D
MetaRNN	Pathogenic	0.91	D;D
MetaSVM	Uncertain	0.27	D
MutationAssessor	Pathogenic	4.8	H;H
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-7.6	D;D
REVEL	Pathogenic	0.66
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;D
Vest4		0.97
MutPred		0.69		Gain of disorder (P = 0.0149);Gain of disorder (P = 0.0149);
MVP		0.87
MPC		2.1
ClinPred		1.0	D
GERP RS		4.1
Varity_R		0.95
gMVP		1.0

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: rs797044864; hg19: chrX-48336469;