dbSNP rs782099600: FTSJ1:p.Ile63Val (chrX-48478514-A-G) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_012280.4(FTSJ1):c.187A>G(p.Ile63Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,207,955 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I63M) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000081 ( 0 hom., 3 hem., cov: 23)

Exomes 𝑓: 0.0000055 ( 0 hom. 1 hem. )

Consequence

FTSJ1
NM_012280.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.35

Publications

0 publications found

Variant links:

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

FTSJ1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.041684628).

BS2

High Hemizygotes in GnomAd4 at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FTSJ1	NM_012280.4 link	c.187A>G	p.Ile63Val	missense_variant	Exon 3 of 13	ENST00000348411.3	NP_036412.1	Q9UET6-1A0A024QYX5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FTSJ1	ENST00000348411.3 link	c.187A>G	p.Ile63Val	missense_variant	Exon 3 of 13	1	NM_012280.4	ENSP00000326948.2		Q9UET6-1

Frequencies

GnomAD3 genomes

AF:

0.0000805

AC:

AN:

111761

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000293

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000165

AC:

AN:

181781

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.000233

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000547

AC:

AN:

1096194

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

361710

show subpopulations

African (AFR)

AF:

0.000228

AC:

AN:

26361

American (AMR)

AF:

0.00

AC:

AN:

35199

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19378

East Asian (EAS)

AF:

0.00

AC:

AN:

30200

South Asian (SAS)

AF:

0.00

AC:

AN:

54073

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40415

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3875

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

840679

Other (OTH)

AF:

0.00

AC:

AN:

46014

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000805

AC:

AN:

111761

Hom.:

Cov.:

AF XY:

0.0000884

AC XY:

AN XY:

33951

show subpopulations

African (AFR)

AF:

0.000293

AC:

AN:

30702

American (AMR)

AF:

0.00

AC:

AN:

10606

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2649

East Asian (EAS)

AF:

0.00

AC:

AN:

3539

South Asian (SAS)

AF:

0.00

AC:

AN:

2687

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6102

Middle Eastern (MID)

AF:

0.00

AC:

AN:

238

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53051

Other (OTH)

AF:

0.00

AC:

AN:

1502

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.542

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000680

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Aug 22, 2016

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.84

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.088

.;T

FATHMM_MKL

Uncertain

0.77

LIST_S2

Benign

0.73

T;T

M_CAP

Benign

0.0052

MetaRNN

Benign

0.042

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.38

N;N

PhyloP100

2.4

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-0.80

N;N

REVEL

Benign

0.042

Sift

Benign

0.17

T;T

Sift4G

Benign

0.24

T;T

Polyphen

0.0

B;B

Vest4

0.12

MVP

0.13

MPC

0.57

ClinPred

0.032

GERP RS

1.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.091

gMVP

0.54

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over