Genetic Variant RIPPLY3:p.Arg88His (chr21-37017897-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_018962.3(RIPPLY3):c.263G>A(p.Arg88His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000062 in 1,613,300 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000099 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000058 ( 1 hom. )

Consequence

RIPPLY3
NM_018962.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.20

Variant links:

Genes affected

RIPPLY3 (HGNC:3047): (ripply transcriptional repressor 3) Predicted to be involved in embryonic pattern specification and negative regulation of transcription by RNA polymerase II. Predicted to act upstream of or within negative regulation of cell population proliferation. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

RIPPLY3 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.12017757).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RIPPLY3	NM_018962.3 link	c.263G>A	p.Arg88His	missense_variant	Exon 4 of 4	ENST00000329553.3	NP_061835.1	P57055-1
RIPPLY3	NM_001317768.2 link	c.11G>A	p.Arg4His	missense_variant	Exon 4 of 4		NP_001304697.1	P57055-2
RIPPLY3	NM_001317777.1 link	c.11G>A	p.Arg4His	missense_variant	Exon 3 of 3		NP_001304706.1	P57055-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
RIPPLY3	ENST00000329553.3 link	c.263G>A	p.Arg88His	missense_variant	Exon 4 of 4	1	NM_018962.3	ENSP00000331734.2	P57055-1
RIPPLY3	ENST00000485272.5 link	n.243G>A		non_coding_transcript_exon_variant	Exon 4 of 4	1
RIPPLY3	ENST00000490393.1 link	n.123G>A		non_coding_transcript_exon_variant	Exon 3 of 3	1

Frequencies

GnomAD3 genomes

AF:

0.0000986

AC:

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000656

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000719

AC:

AN:

250342

Hom.:

AF XY:

0.0000665

AC XY:

AN XY:

135428

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000217

Gnomad SAS exome

AF:

0.000263

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.0000582

AC:

AN:

1461038

Hom.:

Cov.:

AF XY:

0.0000660

AC XY:

AN XY:

726782

show subpopulations

Gnomad4 AFR exome

AF:

0.000269

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000655

Gnomad4 SAS exome

AF:

0.000313

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000162

Gnomad4 OTH exome

AF:

0.0000663

GnomAD4 genome

AF:

0.0000985

AC:

AN:

152262

Hom.:

Cov.:

AF XY:

0.0000940

AC XY:

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.000241

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000774

Hom.:

Bravo

AF:

0.000102

ExAC

AF:

0.000107

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 22, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.263G>A (p.R88H) alteration is located in exon 4 (coding exon 4) of the RIPPLY3 gene. This alteration results from a G to A substitution at nucleotide position 263, causing the arginine (R) at amino acid position 88 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

0.19

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.22

CADD

Benign

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.18

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Benign

0.68

LIST_S2

Benign

0.83

M_CAP

Benign

0.0055

MetaRNN

Benign

0.12

MetaSVM

Benign

-0.70

MutationAssessor

Uncertain

2.3

PrimateAI

Benign

0.47

PROVEAN

Benign

-1.9

REVEL

Benign

0.12

Sift

Benign

0.037

Sift4G

Benign

0.10

Polyphen

1.0

Vest4

0.28

MVP

0.28

MPC

0.29

ClinPred

0.40

GERP RS

4.7

Varity_R

0.12

gMVP

0.075

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over