Genetic Variant RIPPLY3:p.Ile109Asn (chr21-37017960-T-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_018962.3(RIPPLY3):c.326T>A(p.Ile109Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000867 in 1,614,052 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

RIPPLY3
NM_018962.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.41

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.825

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RIPPLY3	NM_018962.3 link	c.326T>A	p.Ile109Asn	missense_variant	Exon 4 of 4	ENST00000329553.3	NP_061835.1	P57055-1
RIPPLY3	NM_001317768.2 link	c.74T>A	p.Ile25Asn	missense_variant	Exon 4 of 4		NP_001304697.1	P57055-2
RIPPLY3	NM_001317777.1 link	c.74T>A	p.Ile25Asn	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.326T>A	p.Ile109Asn	missense_variant	Exon 4 of 4	1	NM_018962.3	ENSP00000331734.2	P57055-1
RIPPLY3	ENST00000485272.5 link	n.306T>A		non_coding_transcript_exon_variant	Exon 4 of 4	1
RIPPLY3	ENST00000490393.1 link	n.186T>A		non_coding_transcript_exon_variant	Exon 3 of 3	1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152170

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251440

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135910

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000889

AC:

AN:

1461882

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000117

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152170

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 14, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.326T>A (p.I109N) alteration is located in exon 4 (coding exon 4) of the RIPPLY3 gene. This alteration results from a T to A substitution at nucleotide position 326, causing the isoleucine (I) at amino acid position 109 to be replaced by an asparagine (N). 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

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.14

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.66

Eigen

Uncertain

0.64

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Uncertain

0.86

LIST_S2

Uncertain

0.90

M_CAP

Benign

0.024

MetaRNN

Pathogenic

0.82

MetaSVM

Uncertain

-0.068

MutationAssessor

Pathogenic

3.3

PrimateAI

Uncertain

0.70

PROVEAN

Pathogenic

-6.8

REVEL

Uncertain

0.32

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.85

MutPred

0.47

Loss of stability (P = 0.0261);

MVP

0.11

MPC

0.51

ClinPred

0.99

GERP RS

4.7

Varity_R

0.88

gMVP

0.45

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

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