X-106903281-A-G

Position:

chrX-106903281-A-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_138382.3(RIPPLY1):c.7T>C(p.Ser3Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000666 in 1,200,371 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 24 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S3F) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000098 ( 0 hom., 1 hem., cov: 24)

Exomes 𝑓: 0.000063 ( 0 hom. 23 hem. )

Consequence

RIPPLY1
NM_138382.3 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.126

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 -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.025779068).

BP6

Variant X-106903281-A-G is Benign according to our data. Variant chrX-106903281-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 2397264.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Hemizygotes in GnomAdExome4 at 23 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
RIPPLY1	NM_138382.3 linkuse as main transcript	c.7T>C	p.Ser3Pro	missense_variant	1/4	ENST00000276173.5
RIPPLY1	NM_001171706.2 linkuse as main transcript	c.7T>C	p.Ser3Pro	missense_variant	1/2
CLDN2	NM_001171092.1 linkuse as main transcript	c.-179+2777A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RIPPLY1	ENST00000276173.5 linkuse as main transcript	c.7T>C	p.Ser3Pro	missense_variant	1/4	1	NM_138382.3	P1	Q0D2K3-1
RIPPLY1	ENST00000411805.1 linkuse as main transcript	c.7T>C	p.Ser3Pro	missense_variant	1/2	1			Q0D2K3-2
CLDN2	ENST00000541806.6 linkuse as main transcript	c.-179+2777A>G		intron_variant		1		P1
MORC4	ENST00000604604.1 linkuse as main transcript	c.112-87495T>C		intron_variant		2

Frequencies

GnomAD3 genomes

AF:

0.0000977

AC:

AN:

112598

Hom.:

Cov.:

AF XY:

0.0000288

AC XY:

AN XY:

34752

show subpopulations

Gnomad AFR

AF:

0.000226

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000937

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00418

Gnomad NFE

AF:

0.0000375

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000764

AC:

AN:

170233

Hom.:

AF XY:

0.0000683

AC XY:

AN XY:

58545

show subpopulations

Gnomad AFR exome

AF:

0.000328

Gnomad AMR exome

AF:

0.000114

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:

0.0000794

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000634

AC:

AN:

1087720

Hom.:

Cov.:

AF XY:

0.0000649

AC XY:

AN XY:

354596

show subpopulations

Gnomad4 AFR exome

AF:

0.000114

Gnomad4 AMR exome

AF:

0.000116

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:

0.0000670

Gnomad4 OTH exome

AF:

0.0000878

GnomAD4 genome

AF:

0.0000976

AC:

AN:

112651

Hom.:

Cov.:

AF XY:

0.0000287

AC XY:

AN XY:

34815

show subpopulations

Gnomad4 AFR

AF:

0.000225

Gnomad4 AMR

AF:

0.0000936

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000375

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000130

Hom.:

Bravo

AF:

0.000106

ESP6500AA

AF:

0.000283

AC:

ESP6500EA

AF:

0.000153

AC:

ExAC

AF:

0.0000909

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 17, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.055

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.83

CADD

Benign

5.4

DANN

Benign

0.88

DEOGEN2

Benign

0.051

T;.

FATHMM_MKL

Benign

0.012

LIST_S2

Benign

0.34

T;T

M_CAP

Benign

0.0083

MetaRNN

Benign

0.026

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.34

N;N

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.47

PROVEAN

Benign

0.46

N;N

REVEL

Benign

0.071

Sift

Pathogenic

0.0

D;D

Sift4G

Benign

1.0

T;T

Polyphen

0.0

B;B

Vest4

0.069

MVP

0.27

MPC

0.032

ClinPred

0.93

GERP RS

-0.66

Varity_R

0.21

gMVP

0.066

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