dbSNP rs768312794: RTL5:p.Arg546Pro (chrX-72129904-C-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The ENST00000609883.3(RTL5):c.1637G>C(p.Arg546Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,208,377 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts 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. R546H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000090 ( 0 hom., 1 hem., cov: 24)

Exomes 𝑓: 0.0000018 ( 0 hom. 1 hem. )

Consequence

RTL5
ENST00000609883.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0770

Publications

2 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: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.17251492).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NHSL2	NM_001013627.3 link	c.281-2175C>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.1637G>C	p.Arg546Pro	missense_variant	Exon 1 of 1	6		ENSP00000476792.1		Q5HYW3
NHSL2	ENST00000633930.2 link	c.281-2175C>G		intron_variant	Intron 1 of 7	5	NM_001013627.3	ENSP00000488668.1		Q5HYW2-1

Frequencies

GnomAD3 genomes

AF:

0.00000897

AC:

AN:

111501

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000378

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:

0.00000558

AC:

AN:

179244

AF XY:

0.0000153

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000137

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000182

AC:

AN:

1096876

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

362368

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

26395

American (AMR)

AF:

0.00

AC:

AN:

35166

Ashkenazi Jewish (ASJ)

AF:

0.0000518

AC:

AN:

19315

East Asian (EAS)

AF:

0.00

AC:

AN:

30203

South Asian (SAS)

AF:

0.00

AC:

AN:

53979

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40453

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4131

European-Non Finnish (NFE)

AF:

0.00000119

AC:

AN:

841196

Other (OTH)

AF:

0.00

AC:

AN:

46038

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000897

AC:

AN:

111501

Hom.:

Cov.:

AF XY:

0.0000297

AC XY:

AN XY:

33705

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30594

American (AMR)

AF:

0.00

AC:

AN:

10646

Ashkenazi Jewish (ASJ)

AF:

0.000378

AC:

AN:

2646

East Asian (EAS)

AF:

0.00

AC:

AN:

3542

South Asian (SAS)

AF:

0.00

AC:

AN:

2632

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6027

Middle Eastern (MID)

AF:

0.00

AC:

AN:

238

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

52994

Other (OTH)

AF:

0.00

AC:

AN:

1501

ExAC

AF:

0.0000165

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Uncertain

0.022

BayesDel_noAF

Benign

-0.21

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.0075

FATHMM_MKL

Benign

0.035

LIST_S2

Benign

0.55

M_CAP

Benign

0.0050

MetaRNN

Benign

0.17

MetaSVM

Benign

-1.0

PhyloP100

-0.077

PrimateAI

Uncertain

0.59

Sift4G

Uncertain

0.047

Polyphen

0.99

Vest4

0.47

MutPred

0.26

Gain of glycosylation at R546 (P = 0.0296);

MVP

0.27

ClinPred

0.29

GERP RS

3.1

Varity_R

0.31

gMVP

0.18

Mutation Taster

=96/4

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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rs768312794

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over