NM_138382.3:c.362A>G

Variant names:

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_138382.3(RIPPLY1):c.362A>G(p.Asn121Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00121 in 1,209,909 control chromosomes in the GnomAD database, including 2 homozygotes. There are 481 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00090 ( 1 hom., 33 hem., cov: 23)

Exomes 𝑓: 0.0012 ( 1 hom. 448 hem. )

Consequence

RIPPLY1
NM_138382.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: 2.91

Variant links:

Genes affected

RIPPLY1 (HGNC:25117): (ripply transcriptional repressor 1) This gene encodes a protein similar to a zebrafish protein which acts as a transcriptional repressor in and is required for somite segmentation in zebrafish embryos (PMID: 16326386). Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2011]

RIPPLY1 links:

CLDN2 (HGNC:2041): (claudin 2) This gene product belongs to the claudin protein family whose members have been identified as major integral membrane proteins localized exclusively at tight junctions. Claudins are expressed in an organ-specific manner and regulate tissue-specific physiologic properties of tight junctions. This protein is expressed in the intestine. Alternatively spliced transcript variants with different 5' untranslated region have been found for this gene.[provided by RefSeq, Jan 2010]

CLDN2 links:

MORC4 (HGNC:23485): (MORC family CW-type zinc finger 4) In human, the four current members of the microrchidia (morc) gene family share an N-terminal ATPase-like ATP-binding region and a CW four-cysteine zinc-finger motif. The protein encoded by this gene also has a nuclear matrix binding domain and a two-stranded coiled-coil motif near its C-terminus. This gene is widely expressed at low levels in normal tissues and has elevated expression in placenta and testis. Alternative splicing results in multiple transcript variants encoding distinct proteins. [provided by RefSeq, Jan 2010]

MORC4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.020251542).

BP6

Variant X-106900843-T-C is Benign according to our data. Variant chrX-106900843-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 725965.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}. Variant chrX-106900843-T-C is described in Lovd as [Likely_benign].

BS2

High Hemizygotes in GnomAd4 at 33 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RIPPLY1	NM_138382.3 link	c.362A>G	p.Asn121Ser	missense_variant	Exon 4 of 4	ENST00000276173.5	NP_612391.1	Q0D2K3-1
RIPPLY1	NM_001171706.2 link	c.221A>G	p.Asn74Ser	missense_variant	Exon 2 of 2		NP_001165177.1	Q0D2K3-2
CLDN2	NM_001171092.1 link	c.-179+339T>C		intron_variant	Intron 1 of 1		NP_001164563.1	P57739

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
RIPPLY1	ENST00000276173.5 link	c.362A>G	p.Asn121Ser	missense_variant	Exon 4 of 4	1	NM_138382.3	ENSP00000276173.4	Q0D2K3-1
RIPPLY1	ENST00000411805.1 link	c.221A>G	p.Asn74Ser	missense_variant	Exon 2 of 2	1		ENSP00000400539.1	Q0D2K3-2
CLDN2	ENST00000541806.6 link	c.-179+339T>C		intron_variant	Intron 1 of 1	1		ENSP00000441283.1	P57739
MORC4	ENST00000604604.1 link	c.111-85057A>G		intron_variant	Intron 1 of 1	2		ENSP00000474750.1	S4R3U3

Frequencies

GnomAD3 genomes

AF:

0.000903

AC:

101

AN:

111805

Hom.:

Cov.:

AF XY:

0.000971

AC XY:

AN XY:

33981

show subpopulations

Gnomad AFR

AF:

0.000196

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000947

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:

0.00175

Gnomad OTH

AF:

0.000665

GnomAD3 exomes

AF:

0.000811

AC:

147

AN:

181245

Hom.:

AF XY:

0.000877

AC XY:

AN XY:

67309

show subpopulations

Gnomad AFR exome

AF:

0.000162

Gnomad AMR exome

AF:

0.0000731

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:

0.00174

Gnomad OTH exome

AF:

0.000449

GnomAD4 exome

AF:

0.00124

AC:

1358

AN:

1098052

Hom.:

Cov.:

AF XY:

0.00123

AC XY:

448

AN XY:

363482

show subpopulations

Gnomad4 AFR exome

AF:

0.000114

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:

0.0000494

Gnomad4 NFE exome

AF:

0.00156

Gnomad4 OTH exome

AF:

0.000911

GnomAD4 genome

AF:

0.000903

AC:

101

AN:

111857

Hom.:

Cov.:

AF XY:

0.000969

AC XY:

AN XY:

34043

show subpopulations

Gnomad4 AFR

AF:

0.000195

Gnomad4 AMR

AF:

0.0000946

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00175

Gnomad4 OTH

AF:

0.000657

Alfa

AF:

0.00148

Hom.:

Bravo

AF:

0.000680

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00139

AC:

ExAC

AF:

0.000728

AC:

EpiCase

AF:

0.000873

EpiControl

AF:

0.00154

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:4

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified

Uncertain:1

Sep 15, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.362A>G (p.N121S) alteration is located in exon 4 (coding exon 4) of the RIPPLY1 gene. This alteration results from a A to G substitution at nucleotide position 362, causing the asparagine (N) at amino acid position 121 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

RIPPLY1-related disorder

Benign:1

Oct 27, 2022

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.61

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.54

D;.

FATHMM_MKL

Uncertain

0.83

LIST_S2

Uncertain

0.87

D;D

M_CAP

Benign

0.0092

MetaRNN

Benign

0.020

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.2

M;.

PrimateAI

Benign

0.47

PROVEAN

Pathogenic

-4.8

D;D

REVEL

Benign

0.073

Sift

Benign

0.24

T;T

Sift4G

Benign

0.089

T;T

Polyphen

0.13

B;P

Vest4

0.16

MVP

0.63

MPC

0.10

ClinPred

0.061

GERP RS

2.5

Varity_R

0.17

gMVP

0.25

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