Genetic Variant RTL5:p.Ala490Ser (chrX-72130073-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The ENST00000609883.3(RTL5):c.1468G>T(p.Ala490Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000662 in 1,208,927 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A490P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 0 hem., cov: 21)

Exomes 𝑓: 0.0000055 ( 0 hom. 0 hem. )

Consequence

RTL5
ENST00000609883.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.691

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.090028524).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NHSL2	NM_001013627.3 link	c.281-2006C>A		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.1468G>T	p.Ala490Ser	missense_variant	Exon 1 of 1	6		ENSP00000476792.1		Q5HYW3
NHSL2	ENST00000633930.2 link	c.281-2006C>A		intron_variant	Intron 1 of 7	5	NM_001013627.3	ENSP00000488668.1		Q5HYW2-1

Frequencies

GnomAD3 genomes

AF:

0.0000180

AC:

AN:

110912

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000947

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:

0.0000165

AC:

AN:

181458

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000731

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:

0.00000546

AC:

AN:

1098015

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

363441

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26402

American (AMR)

AF:

0.0000568

AC:

AN:

35199

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19378

East Asian (EAS)

AF:

0.00

AC:

AN:

30206

South Asian (SAS)

AF:

0.00

AC:

AN:

54131

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40521

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4137

European-Non Finnish (NFE)

AF:

0.00000475

AC:

AN:

841963

Other (OTH)

AF:

0.00

AC:

AN:

46078

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000180

AC:

AN:

110912

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33124

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30431

American (AMR)

AF:

0.0000947

AC:

AN:

10563

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2642

East Asian (EAS)

AF:

0.00

AC:

AN:

3498

South Asian (SAS)

AF:

0.00

AC:

AN:

2569

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5928

Middle Eastern (MID)

AF:

0.00

AC:

AN:

239

European-Non Finnish (NFE)

AF:

0.0000189

AC:

AN:

52876

Other (OTH)

AF:

0.00

AC:

AN:

1484

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000323

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000826

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.59

CADD

Benign

3.0

(source)

DANN

Benign

0.80

DEOGEN2

Benign

0.0046

FATHMM_MKL

Benign

0.16

LIST_S2

Benign

0.49

M_CAP

Benign

0.0028

MetaRNN

Benign

0.090

MetaSVM

Benign

-1.0

PhyloP100

0.69

PrimateAI

Benign

0.25

Sift4G

Benign

0.35

Polyphen

0.79

Vest4

0.14

MutPred

0.20

Loss of helix (P = 0.0167);

MVP

0.10

ClinPred

0.049

GERP RS

2.1

Varity_R

0.057

gMVP

0.13

Mutation Taster

=98/2

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-72130073-C-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over