rs2070991

Variant names:

• chrX-48481597-C-T
• rs2070991
• NM_012280.4:c.572-35C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_012280.4(FTSJ1):​c.572-35C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.225 in 1,146,737 control chromosomes in the GnomAD database, including 21,056 homozygotes. There are 82,322 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.23 (2302 hom., 7789 hem., cov: 23)
  • Exomes 𝑓: 0.22 (18754 hom. 74533 hem.)
• Consequence: FTSJ1 NM_012280.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.00200
• Publications: 6 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: Benign. The variant received -20 ACMG points.

• BP4: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 0 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant X-48481597-C-T is Benign according to our data. Variant chrX-48481597-C-T is described in ClinVar as Benign. ClinVar VariationId is 1285660.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.446 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FTSJ1	NM_012280.4	c.572-35C>T		intron_variant	Intron 8 of 12	ENST00000348411.3	NP_036412.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FTSJ1	ENST00000348411.3	c.572-35C>T		intron_variant	Intron 8 of 12	1	NM_012280.4	ENSP00000326948.2

Frequencies

GnomAD3 genomes AF: 0.231 AC: 25860 AN: 111801 Hom.: 2304 Cov.: 23

Gnomad AFR AF: 0.251

Gnomad AMI AF: 0.187

Gnomad AMR AF: 0.315

Gnomad ASJ AF: 0.201

Gnomad EAS AF: 0.465

Gnomad SAS AF: 0.347

Gnomad FIN AF: 0.164

Gnomad MID AF: 0.148

Gnomad NFE AF: 0.192

Gnomad OTH AF: 0.243

GnomAD2 exomes AF: 0.263 AC: 47020 AN: 179091 AF XY: 0.257

Gnomad AFR exome AF: 0.254

Gnomad AMR exome AF: 0.382

Gnomad ASJ exome AF: 0.208

Gnomad EAS exome AF: 0.471

Gnomad FIN exome AF: 0.168

Gnomad NFE exome AF: 0.192

Gnomad OTH exome AF: 0.241

GnomAD4 exome AF: 0.224 AC: 232085 AN: 1034885 Hom.: 18754 Cov.: 25 AF XY: 0.237 AC XY: 74533 AN XY: 314697

African (AFR) AF: 0.259 AC: 6555 AN: 25265

American (AMR) AF: 0.374 AC: 13019 AN: 34824

Ashkenazi Jewish (ASJ) AF: 0.211 AC: 4015 AN: 18991

East Asian (EAS) AF: 0.445 AC: 13313 AN: 29944

South Asian (SAS) AF: 0.353 AC: 18587 AN: 52706

European-Finnish (FIN) AF: 0.177 AC: 7146 AN: 40433

Middle Eastern (MID) AF: 0.213 AC: 850 AN: 3993

European-Non Finnish (NFE) AF: 0.201 AC: 158095 AN: 784739

Other (OTH) AF: 0.239 AC: 10505 AN: 43990

GnomAD4 genome AF: 0.231 AC: 25860 AN: 111852 Hom.: 2302 Cov.: 23 AF XY: 0.228 AC XY: 7789 AN XY: 34088

African (AFR) AF: 0.251 AC: 7739 AN: 30812

American (AMR) AF: 0.314 AC: 3334 AN: 10612

Ashkenazi Jewish (ASJ) AF: 0.201 AC: 531 AN: 2646

East Asian (EAS) AF: 0.465 AC: 1630 AN: 3504

South Asian (SAS) AF: 0.345 AC: 940 AN: 2723

European-Finnish (FIN) AF: 0.164 AC: 1001 AN: 6101

Middle Eastern (MID) AF: 0.140 AC: 30 AN: 214

European-Non Finnish (NFE) AF: 0.192 AC: 10155 AN: 53027

Other (OTH) AF: 0.243 AC: 373 AN: 1533

Alfa AF: 0.211 Hom.: 1828

Bravo AF: 0.250

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 19, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	1.1
DANN	Benign	0.73
PhyloP100		0.0020
BranchPoint Hunter		0.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2070991; hg19: chrX-48339985; COSMIC: COSV50025579; COSMIC: COSV50025579;