Genetic Variant RTL5:p.Asn334Ser (chrX-72130540-T-C) – ACMG Classification: Benign (-8 pts)

Variant summary

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

The NM_001405151.1(RTL5):c.1001A>G(p.Asn334Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000653 in 1,208,951 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 19 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00022 ( 0 hom., 5 hem., cov: 22)

Exomes 𝑓: 0.000050 ( 0 hom. 14 hem. )

Consequence

RTL5
NM_001405151.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.507

Publications

0 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 -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.015117884).

BS2

High Hemizygotes in GnomAd4 at 5 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001405151.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RTL5	NM_001405151.1	MANE Select	c.1001A>G	p.Asn334Ser	missense	Exon 1 of 1	NP_001392080.1	Q5HYW3
NHSL2	NM_001013627.3	MANE Select	c.281-1539T>C		intron	N/A	NP_001013649.2	Q5HYW2-1
RTL5	NM_001024455.4		c.1001A>G	p.Asn334Ser	missense	Exon 1 of 2	NP_001019626.1	Q5HYW3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RTL5	ENST00000609883.3	TSL:6 MANE Select	c.1001A>G	p.Asn334Ser	missense	Exon 1 of 1	ENSP00000476792.1	Q5HYW3
NHSL2	ENST00000633930.2	TSL:5 MANE Select	c.281-1539T>C		intron	N/A	ENSP00000488668.1	Q5HYW2-1
RTL5	ENST00000479991.1	TSL:1	n.1001A>G		non_coding_transcript_exon	Exon 1 of 2	ENSP00000418667.1	Q5HYW3

Frequencies

GnomAD3 genomes

AF:

0.000216

AC:

AN:

111132

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000722

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000192

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:

0.0000826

AC:

AN:

181596

AF XY:

0.000104

show subpopulations

Gnomad AFR exome

AF:

0.000807

Gnomad AMR exome

AF:

0.0000365

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000492

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000501

AC:

AN:

1097819

Hom.:

Cov.:

AF XY:

0.0000385

AC XY:

AN XY:

363249

show subpopulations

African (AFR)

AF:

0.000530

AC:

AN:

26398

American (AMR)

AF:

0.0000568

AC:

AN:

35206

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19383

East Asian (EAS)

AF:

0.00

AC:

AN:

30203

South Asian (SAS)

AF:

0.00

AC:

AN:

54140

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40521

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4133

European-Non Finnish (NFE)

AF:

0.0000380

AC:

AN:

841758

Other (OTH)

AF:

0.000152

AC:

AN:

46077

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

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:

0.000216

AC:

AN:

111132

Hom.:

Cov.:

AF XY:

0.000150

AC XY:

AN XY:

33324

show subpopulations

African (AFR)

AF:

0.000722

AC:

AN:

30486

American (AMR)

AF:

0.000192

AC:

AN:

10422

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2637

East Asian (EAS)

AF:

0.00

AC:

AN:

3559

South Asian (SAS)

AF:

0.00

AC:

AN:

2610

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5934

Middle Eastern (MID)

AF:

0.00

AC:

AN:

236

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53064

Other (OTH)

AF:

0.00

AC:

AN:

1497

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

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:

0.000214

Hom.:

Bravo

AF:

0.000238

ESP6500AA

AF:

0.000900

AC:

ESP6500EA

AF:

0.000154

AC:

ExAC

AF:

0.000132

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000237

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.78

BayesDel_noAF

Benign

-0.97

CADD

Benign

(source)

DANN

Benign

0.73

DEOGEN2

Benign

0.0038

FATHMM_MKL

Benign

0.043

LIST_S2

Benign

0.34

M_CAP

Benign

0.0050

MetaRNN

Benign

0.015

MetaSVM

Benign

-1.0

PhyloP100

0.51

PrimateAI

Benign

0.30

Sift4G

Benign

0.13

Polyphen

0.0050

Vest4

0.13

MVP

0.014

ClinPred

0.0084

GERP RS

0.23

Varity_R

0.039

gMVP

0.30

Mutation Taster

=100/0

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over