Genetic Variant RTL9:p.Ser1121Leu (chrX-110453979-C-T) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001385449.1(RTL9):c.3362C>T(p.Ser1121Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000165 in 1,210,245 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 7 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.000017 ( 0 hom. 7 hem. )

Consequence

RTL9
NM_001385449.1 missense

Scores

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: 2.42

Publications

2 publications found

Variant links:

Genes affected

RTL9 (HGNC:29245): (retrotransposon Gag like 9)

RTL9 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.06985766).

BS2

High Hemizygotes in GnomAdExome4 at 7 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RTL9	NM_001385449.1 link	c.3362C>T	p.Ser1121Leu	missense_variant	Exon 3 of 4	ENST00000520821.6	NP_001372378.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
RTL9	ENST00000520821.6 link	c.3362C>T	p.Ser1121Leu	missense_variant	Exon 3 of 4	4	NM_001385449.1	ENSP00000430395.2	Q8NET4E5RKA1
RTL9	ENST00000465301.2 link	c.3362C>T	p.Ser1121Leu	missense_variant	Exon 3 of 4	1		ENSP00000419786.2	Q8NET4
RTL9	ENST00000540313.1 link	c.3362C>T	p.Ser1121Leu	missense_variant	Exon 1 of 2	2		ENSP00000441452.1	Q8NET4

Frequencies

GnomAD3 genomes

AF:

0.00000893

AC:

AN:

112038

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000940

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:

0.0000164

AC:

AN:

182948

AF XY:

0.0000148

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000729

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000123

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000173

AC:

AN:

1098207

Hom.:

Cov.:

AF XY:

0.0000193

AC XY:

AN XY:

363569

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26401

American (AMR)

AF:

0.0000568

AC:

AN:

35207

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19386

East Asian (EAS)

AF:

0.00

AC:

AN:

30206

South Asian (SAS)

AF:

0.00

AC:

AN:

54149

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40508

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4137

European-Non Finnish (NFE)

AF:

0.0000190

AC:

AN:

842115

Other (OTH)

AF:

0.0000217

AC:

AN:

46098

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.446

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000893

AC:

AN:

112038

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34186

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30769

American (AMR)

AF:

0.0000940

AC:

AN:

10637

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2639

East Asian (EAS)

AF:

0.00

AC:

AN:

3573

South Asian (SAS)

AF:

0.00

AC:

AN:

2630

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6153

Middle Eastern (MID)

AF:

0.00

AC:

AN:

239

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53206

Other (OTH)

AF:

0.00

AC:

AN:

1509

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Spinocerebellar ataxia, X-linked

Uncertain:1

Vavilov Institute of General Genetics RAS, Laboratory of Evolutional Genomics

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:case-control

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.77

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0082

T;T

FATHMM_MKL

Benign

0.064

LIST_S2

Benign

0.53

.;T

M_CAP

Benign

0.047

MetaRNN

Benign

0.070

T;T

MetaSVM

Benign

-1.1

PhyloP100

2.4

PrimateAI

Benign

0.31

PROVEAN

Benign

-1.1

N;N

REVEL

Benign

0.039

Sift

Uncertain

0.0050

D;D

Sift4G

Benign

0.14

T;T

Polyphen

0.052

B;B

Vest4

0.17

MutPred

0.20

Loss of glycosylation at S1121 (P = 0.0057);Loss of glycosylation at S1121 (P = 0.0057);

MVP

0.068

MPC

0.049

ClinPred

0.27

GERP RS

4.3

Varity_R

0.083

gMVP

0.26

Mutation Taster

=97/3

polymorphism

(source)

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

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chrX-110453979-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over