Genetic Variant RTL5:p.Ser420Arg (chrX-72130283-T-G) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000609883.3(RTL5):c.1258A>C(p.Ser420Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.108 in 1,197,040 control chromosomes in the GnomAD database, including 7,681 homozygotes. There are 42,413 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 11/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S420N) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.093 ( 656 hom., 2903 hem., cov: 21)

Exomes 𝑓: 0.11 ( 7025 hom. 39510 hem. )

Consequence

RTL5
ENST00000609883.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.153

Publications

15 publications found

Variant links:

Genes affected

RTL5 (HGNC:29430): (retrotransposon Gag like 5)

RTL5 links:

NHSL2 (HGNC:33737): (NHS like 2) Predicted to enable calcium ion binding activity. Predicted to be involved in cell differentiation. Predicted to be active in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

NHSL2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.180158E-4).

BP6

Variant X-72130283-T-G is Benign according to our data. Variant chrX-72130283-T-G is described in ClinVar as [Benign]. Clinvar id is 1300264.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.481 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NHSL2	NM_001013627.3 link	c.281-1796T>G		intron_variant	Intron 1 of 7	ENST00000633930.2	NP_001013649.2	Q5HYW2-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RTL5	ENST00000609883.3 link	c.1258A>C	p.Ser420Arg	missense_variant	Exon 1 of 1	6		ENSP00000476792.1		Q5HYW3
NHSL2	ENST00000633930.2 link	c.281-1796T>G		intron_variant	Intron 1 of 7	5	NM_001013627.3	ENSP00000488668.1		Q5HYW2-1

Frequencies

GnomAD3 genomes

AF:

0.0928

AC:

10068

AN:

108517

Hom.:

660

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0199

Gnomad AMI

AF:

0.0893

Gnomad AMR

AF:

0.204

Gnomad ASJ

AF:

0.0592

Gnomad EAS

AF:

0.501

Gnomad SAS

AF:

0.163

Gnomad FIN

AF:

0.0857

Gnomad MID

AF:

0.0470

Gnomad NFE

AF:

0.0860

Gnomad OTH

AF:

0.0838

GnomAD2 exomes

AF:

0.155

AC:

27918

AN:

180056

AF XY:

0.144

show subpopulations

Gnomad AFR exome

AF:

0.0177

Gnomad AMR exome

AF:

0.312

Gnomad ASJ exome

AF:

0.0558

Gnomad EAS exome

AF:

0.505

Gnomad FIN exome

AF:

0.0916

Gnomad NFE exome

AF:

0.0885

Gnomad OTH exome

AF:

0.126

GnomAD4 exome

AF:

0.110

AC:

119299

AN:

1088466

Hom.:

7025

Cov.:

AF XY:

0.112

AC XY:

39510

AN XY:

354346

show subpopulations

African (AFR)

AF:

0.0144

AC:

377

AN:

26203

American (AMR)

AF:

0.300

AC:

10520

AN:

35056

Ashkenazi Jewish (ASJ)

AF:

0.0567

AC:

1095

AN:

19304

East Asian (EAS)

AF:

0.521

AC:

15703

AN:

30162

South Asian (SAS)

AF:

0.153

AC:

8240

AN:

53897

European-Finnish (FIN)

AF:

0.0957

AC:

3872

AN:

40466

Middle Eastern (MID)

AF:

0.0821

AC:

338

AN:

4117

European-Non Finnish (NFE)

AF:

0.0889

AC:

74057

AN:

833494

Other (OTH)

AF:

0.111

AC:

5097

AN:

45767

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

3983

7966

11948

15931

19914

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0926

AC:

10058

AN:

108574

Hom.:

656

Cov.:

AF XY:

0.0937

AC XY:

2903

AN XY:

30998

show subpopulations

African (AFR)

AF:

0.0199

AC:

593

AN:

29805

American (AMR)

AF:

0.204

AC:

2078

AN:

10178

Ashkenazi Jewish (ASJ)

AF:

0.0592

AC:

154

AN:

2602

East Asian (EAS)

AF:

0.501

AC:

1678

AN:

3352

South Asian (SAS)

AF:

0.161

AC:

385

AN:

2389

European-Finnish (FIN)

AF:

0.0857

AC:

483

AN:

5636

Middle Eastern (MID)

AF:

0.0421

AC:

AN:

214

European-Non Finnish (NFE)

AF:

0.0860

AC:

4493

AN:

52240

Other (OTH)

AF:

0.0841

AC:

125

AN:

1486

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

281

562

843

1124

1405

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0965

Hom.:

7523

Bravo

AF:

0.105

TwinsUK

AF:

0.0858

AC:

318

ALSPAC

AF:

0.0893

AC:

258

ESP6500AA

AF:

0.0212

AC:

ESP6500EA

AF:

0.0876

AC:

578

ExAC

AF:

0.143

AC:

17368

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Sep 25, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.81

BayesDel_noAF

Benign

-0.79

CADD

Benign

1.1

(source)

DANN

Benign

0.82

DEOGEN2

Benign

0.0025

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.37

MetaRNN

Benign

0.00012

MetaSVM

Benign

-0.90

PhyloP100

0.15

PrimateAI

Benign

0.29

Sift4G

Uncertain

0.053

Polyphen

0.080

Vest4

0.027

MutPred

0.089

Loss of phosphorylation at S420 (P = 3e-04);

ClinPred

0.00091

GERP RS

1.3

Varity_R

0.097

gMVP

0.022

Mutation Taster

=100/0

polymorphism (auto)

(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-72130283-T-G

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