chrX-48478488-G-A

Variant names:

• chrX-48478488-G-A
• rs1556967227
• NM_012280.4:c.161G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PM5

The NM_012280.4(FTSJ1):​c.161G>A​(p.Ser54Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000000912 in 1,096,662 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S54T) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: FTSJ1 NM_012280.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.03
• Publications: 0 publications found

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]

FTSJ1 Gene-Disease associations (from GenCC):

• intellectual disability, X-linked 9

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• X-linked complex neurodevelopmental disorder

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• non-syndromic X-linked intellectual disability

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-48478488-G-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 520557.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012280.4. 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
	FTSJ1	NM_012280.4	MANE Select	c.161G>A	p.Ser54Asn	missense	Exon 3 of 13	NP_036412.1	A0A024QYX5
	FTSJ1	NM_001441197.1		c.161G>A	p.Ser54Asn	missense	Exon 3 of 11	NP_001428126.1
	FTSJ1	NM_001441198.1		c.161G>A	p.Ser54Asn	missense	Exon 4 of 12	NP_001428127.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FTSJ1	ENST00000348411.3	TSL:1 MANE Select	c.161G>A	p.Ser54Asn	missense	Exon 3 of 13	ENSP00000326948.2	Q9UET6-1
	FTSJ1	ENST00000898808.1		c.161G>A	p.Ser54Asn	missense	Exon 4 of 14	ENSP00000568867.1
	FTSJ1	ENST00000898812.1		c.161G>A	p.Ser54Asn	missense	Exon 3 of 13	ENSP00000568871.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.12e-7 AC: 1 AN: 1096662 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 362358

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 26365

American (AMR) AF: 0.00 AC: 0 AN: 35196

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19378

East Asian (EAS) AF: 0.00 AC: 0 AN: 30206

South Asian (SAS) AF: 0.00 AC: 0 AN: 54089

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40428

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3656

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 841338

Other (OTH) AF: 0.00 AC: 0 AN: 46006

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	T
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.074	D
MetaRNN	Uncertain	0.74	D
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Pathogenic	4.5	H
PhyloP100		7.0
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.38
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.96	D
Vest4		0.54
MutPred		0.76		Loss of disorder (P = 0.0869)
MVP		0.56
MPC		1.6
ClinPred		1.0	D
GERP RS		4.4
Varity_R		0.91
gMVP		0.98
Mutation Taster		=25/75	disease causing

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: rs1556967227; hg19: chrX-48336876;