Genetic Variant RGS5-AS1:n.1754C>A (chr1-163212144-C-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The ENST00000415437.1(RGS5-AS1):n.1754C>A variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.137 in 152,132 control chromosomes in the GnomAD database, including 1,499 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.14 ( 1499 hom., cov: 32)

Exomes 𝑓: 0.17 ( 0 hom. )

Consequence

RGS5-AS1
ENST00000415437.1 non_coding_transcript_exon

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.355

Publications

5 publications found

Variant links:

Genes affected

RGS5-AS1 (HGNC:40504): (RGS5 antisense RNA 1)

RGS5-AS1 links:

RGS5 (HGNC:10001): (regulator of G protein signaling 5) This locus represents naturally occurring readthrough transcription between the neighboring LOC127814295 (uncharacterized LOC127814295) and RGS5 (regulator of G-protein signaling 5) genes on chromosome 1. Some variants of the readthrough transcript encode novel proteins with unique N-termini. [provided by RefSeq, Nov 2022]

RGS5 Gene-Disease associations (from GenCC):

essential hypertension, genetic
Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

RGS5 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.75).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.147 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	Protein
RGS5-AS1	NR_110699.1 link	n.1754C>A	non_coding_transcript_exon_variant	Exon 4 of 4
RGS5	NM_001414472.1 link	c.65+36386G>T	intron_variant	Intron 3 of 6	NP_001401401.1
RGS5	NM_001414473.1 link	c.65+36386G>T	intron_variant	Intron 5 of 8	NP_001401402.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	Protein	UniProt
RGS5-AS1	ENST00000415437.1 link	n.1754C>A	non_coding_transcript_exon_variant	Exon 4 of 4	2
RGS5	ENST00000367903.7 link	c.69+5382G>T	intron_variant	Intron 1 of 5	3	ENSP00000356879.3	B1APM2
RGS5	ENST00000618415.4 link	c.-280-43776G>T	intron_variant	Intron 2 of 5	4	ENSP00000480891.1	O15539-2

Frequencies

GnomAD3 genomes

AF:

0.137

AC:

20869

AN:

152008

Hom.:

1500

Cov.:

show subpopulations

Gnomad AFR

AF:

0.134

Gnomad AMI

AF:

0.109

Gnomad AMR

AF:

0.140

Gnomad ASJ

AF:

0.133

Gnomad EAS

AF:

0.0390

Gnomad SAS

AF:

0.0734

Gnomad FIN

AF:

0.156

Gnomad MID

AF:

0.0886

Gnomad NFE

AF:

0.149

Gnomad OTH

AF:

0.133

GnomAD4 exome

AF:

0.167

AC:

AN:

Hom.:

Cov.:

AF XY:

0.167

AC XY:

AN XY:

show subpopulations

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

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AF:

0.00

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.250

AC:

AN:

Other (OTH)

AC:

AN:

⚠️ 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: 0.275

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.137

AC:

20880

AN:

152126

Hom.:

1499

Cov.:

AF XY:

0.137

AC XY:

10156

AN XY:

74376

show subpopulations

African (AFR)

AF:

0.133

AC:

5540

AN:

41508

American (AMR)

AF:

0.140

AC:

2135

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.133

AC:

462

AN:

3466

East Asian (EAS)

AF:

0.0387

AC:

201

AN:

5188

South Asian (SAS)

AF:

0.0738

AC:

356

AN:

4822

European-Finnish (FIN)

AF:

0.156

AC:

1649

AN:

10576

Middle Eastern (MID)

AF:

0.0918

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.149

AC:

10133

AN:

67970

Other (OTH)

AF:

0.132

AC:

278

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

914

1829

2743

3658

4572

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

236

472

708

944

1180

<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:

0.139

Hom.:

2535

Bravo

AF:

0.136

Asia WGS

AF:

0.0790

AC:

273

AN:

3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.75

CADD

Benign

6.6

(source)

DANN

Benign

0.82

PhyloP100

0.35

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over