dbSNP rs768771267: RTL5:p.Asp422His (chrX-72130277-C-G) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The ENST00000609883.3(RTL5):c.1264G>C(p.Asp422His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000266 in 1,200,834 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 10 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 0.000027 ( 0 hom., 1 hem., cov: 21)

Exomes 𝑓: 0.000027 ( 0 hom. 9 hem. )

Consequence

RTL5
ENST00000609883.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.45

Publications

1 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 -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.08857635).

BS2

High Hemizygotes in GnomAdExome4 at 9 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NHSL2	NM_001013627.3 link	c.281-1802C>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.1264G>C	p.Asp422His	missense_variant	Exon 1 of 1	6		ENSP00000476792.1		Q5HYW3
NHSL2	ENST00000633930.2 link	c.281-1802C>G		intron_variant	Intron 1 of 7	5	NM_001013627.3	ENSP00000488668.1		Q5HYW2-1

Frequencies

GnomAD3 genomes

AF:

0.0000274

AC:

AN:

109535

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:

0.0000571

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000166

AC:

AN:

180899

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000370

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000266

AC:

AN:

1091299

Hom.:

Cov.:

AF XY:

0.0000252

AC XY:

AN XY:

356935

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26287

American (AMR)

AF:

0.00

AC:

AN:

35172

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19321

East Asian (EAS)

AF:

0.00

AC:

AN:

30168

South Asian (SAS)

AF:

0.00

AC:

AN:

53918

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40487

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4119

European-Non Finnish (NFE)

AF:

0.0000347

AC:

AN:

835973

Other (OTH)

AF:

0.00

AC:

AN:

45854

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

GnomAD4 genome

AF:

0.0000274

AC:

AN:

109535

Hom.:

Cov.:

AF XY:

0.0000315

AC XY:

AN XY:

31785

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

29971

American (AMR)

AF:

0.00

AC:

AN:

10303

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2618

East Asian (EAS)

AF:

0.00

AC:

AN:

3487

South Asian (SAS)

AF:

0.00

AC:

AN:

2439

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5813

Middle Eastern (MID)

AF:

0.00

AC:

AN:

236

European-Non Finnish (NFE)

AF:

0.0000571

AC:

AN:

52509

Other (OTH)

AF:

0.00

AC:

AN:

1479

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000130

Hom.:

Bravo

AF:

0.0000340

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 26, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1264G>C (p.D422H) alteration is located in exon 1 (coding exon 1) of the RGAG4 gene. This alteration results from a G to C substitution at nucleotide position 1264, causing the aspartic acid (D) at amino acid position 422 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.58

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.0027

FATHMM_MKL

Benign

0.23

LIST_S2

Benign

0.40

M_CAP

Benign

0.0034

MetaRNN

Benign

0.089

MetaSVM

Benign

-1.0

PhyloP100

1.4

PrimateAI

Benign

0.28

Sift4G

Pathogenic

0.0010

Polyphen

0.92

Vest4

0.14

MVP

0.014

ClinPred

0.068

GERP RS

3.2

Varity_R

0.060

gMVP

0.059

Mutation Taster

=99/1

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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rs768771267

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