Genetic Variant RTL5:p.Ala477Thr (chrX-72130112-C-T) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_001405151.1(RTL5):c.1429G>A(p.Ala477Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000232 in 1,208,632 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 9 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 Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A477P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000090 ( 0 hom., 0 hem., cov: 22)

Exomes 𝑓: 0.000025 ( 0 hom. 9 hem. )

Consequence

RTL5
NM_001405151.1 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.412

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 -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.030770808).

BP6

Variant X-72130112-C-T is Benign according to our data. Variant chrX-72130112-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2511349.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Hemizygotes in GnomAdExome4 at 9 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.1429G>A	p.Ala477Thr	missense	Exon 1 of 1	NP_001392080.1	Q5HYW3
NHSL2	NM_001013627.3	MANE Select	c.281-1967C>T		intron	N/A	NP_001013649.2	Q5HYW2-1
RTL5	NM_001024455.4		c.1429G>A	p.Ala477Thr	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.1429G>A	p.Ala477Thr	missense	Exon 1 of 1	ENSP00000476792.1	Q5HYW3
NHSL2	ENST00000633930.2	TSL:5 MANE Select	c.281-1967C>T		intron	N/A	ENSP00000488668.1	Q5HYW2-1
RTL5	ENST00000479991.1	TSL:1	n.1429G>A		non_coding_transcript_exon	Exon 1 of 2	ENSP00000418667.1	Q5HYW3

Frequencies

GnomAD3 genomes

AF:

0.00000905

AC:

AN:

110519

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000189

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000385

AC:

AN:

181652

AF XY:

0.0000592

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.0000737

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000246

AC:

AN:

1098113

Hom.:

Cov.:

AF XY:

0.0000248

AC XY:

AN XY:

363539

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26402

American (AMR)

AF:

0.0000852

AC:

AN:

35207

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19385

East Asian (EAS)

AF:

0.00

AC:

AN:

30206

South Asian (SAS)

AF:

0.0000185

AC:

AN:

54148

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40522

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4136

European-Non Finnish (NFE)

AF:

0.0000261

AC:

AN:

842025

Other (OTH)

AF:

0.0000217

AC:

AN:

46082

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

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:

0.00000905

AC:

AN:

110519

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

32721

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30355

American (AMR)

AF:

0.00

AC:

AN:

10473

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2643

East Asian (EAS)

AF:

0.00

AC:

AN:

3476

South Asian (SAS)

AF:

0.00

AC:

AN:

2543

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5831

Middle Eastern (MID)

AF:

0.00

AC:

AN:

236

European-Non Finnish (NFE)

AF:

0.0000189

AC:

AN:

52800

Other (OTH)

AF:

0.00

AC:

AN:

1481

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.0000495

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000178

ClinVar

ClinVar submissions

Significance:Likely benign

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

0.082

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.97

CADD

Benign

1.1

(source)

DANN

Benign

0.80

DEOGEN2

Benign

0.0011

FATHMM_MKL

Benign

0.030

LIST_S2

Benign

0.51

M_CAP

Benign

0.0046

MetaRNN

Benign

0.031

MetaSVM

Benign

-1.0

PhyloP100

0.41

PrimateAI

Benign

0.25

Sift4G

Benign

0.29

Polyphen

0.0060

Vest4

0.023

MutPred

0.11

Gain of phosphorylation at A477 (P = 0.0185)

MVP

0.12

ClinPred

0.028

GERP RS

1.4

Varity_R

0.029

gMVP

0.13

Mutation Taster

=100/0

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over