chrX-106903194-G-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_138382.3(RIPPLY1):c.94C>A(p.Pro32Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00018 in 1,209,733 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 60 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000089 ( 0 hom., 1 hem., cov: 23)

Exomes 𝑓: 0.00019 ( 0 hom. 59 hem. )

Consequence

RIPPLY1
NM_138382.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.73

Publications

1 publications found

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 was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.24010378).

BS2

High Hemizygotes in GnomAdExome4 at 59 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RIPPLY1	NM_138382.3 link	c.94C>A	p.Pro32Thr	missense_variant	Exon 1 of 4	ENST00000276173.5	NP_612391.1	Q0D2K3-1
RIPPLY1	NM_001171706.2 link	c.94C>A	p.Pro32Thr	missense_variant	Exon 1 of 2		NP_001165177.1	Q0D2K3-2
CLDN2	NM_001171092.1 link	c.-179+2690G>T		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.94C>A	p.Pro32Thr	missense_variant	Exon 1 of 4	1	NM_138382.3	ENSP00000276173.4	Q0D2K3-1
RIPPLY1	ENST00000411805.1 link	c.94C>A	p.Pro32Thr	missense_variant	Exon 1 of 2	1		ENSP00000400539.1	Q0D2K3-2
CLDN2	ENST00000541806.6 link	c.-179+2690G>T		intron_variant	Intron 1 of 1	1		ENSP00000441283.1	P57739
MORC4	ENST00000604604.1 link	c.111-87408C>A		intron_variant	Intron 1 of 1	2		ENSP00000474750.1	S4R3U3

Frequencies

GnomAD3 genomes

AF:

0.0000888

AC:

AN:

112644

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000322

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:

0.000169

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000564

AC:

AN:

177334

AF XY:

0.0000308

show subpopulations

Gnomad AFR exome

AF:

0.000163

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000894

Gnomad OTH exome

AF:

0.000227

GnomAD4 exome

AF:

0.000190

AC:

208

AN:

1097089

Hom.:

Cov.:

AF XY:

0.000163

AC XY:

AN XY:

362583

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26383

American (AMR)

AF:

0.00

AC:

AN:

35159

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19367

East Asian (EAS)

AF:

0.00

AC:

AN:

30177

South Asian (SAS)

AF:

0.00

AC:

AN:

53882

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40491

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4070

European-Non Finnish (NFE)

AF:

0.000242

AC:

204

AN:

841543

Other (OTH)

AF:

0.0000869

AC:

AN:

46017

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000888

AC:

AN:

112644

Hom.:

Cov.:

AF XY:

0.0000287

AC XY:

AN XY:

34800

show subpopulations

African (AFR)

AF:

0.0000322

AC:

AN:

31022

American (AMR)

AF:

0.00

AC:

AN:

10680

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2662

East Asian (EAS)

AF:

0.00

AC:

AN:

3576

South Asian (SAS)

AF:

0.00

AC:

AN:

2730

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6233

Middle Eastern (MID)

AF:

0.00

AC:

AN:

240

European-Non Finnish (NFE)

AF:

0.000169

AC:

AN:

53298

Other (OTH)

AF:

0.00

AC:

AN:

1518

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.0000434

Hom.:

Bravo

AF:

0.0000416

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000153

AC:

ExAC

AF:

0.0000744

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 01, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.94C>A (p.P32T) alteration is located in exon 1 (coding exon 1) of the RIPPLY1 gene. This alteration results from a C to A substitution at nucleotide position 94, causing the proline (P) at amino acid position 32 to be replaced by a threonine (T). 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

0.10

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.20

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.31

T;.

FATHMM_MKL

Benign

0.70

LIST_S2

Benign

0.57

T;T

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.24

T;T

MetaSVM

Benign

-0.52

MutationAssessor

Benign

1.1

L;L

PhyloP100

3.7

PrimateAI

Uncertain

0.55

PROVEAN

Uncertain

-2.6

D;D

REVEL

Benign

0.14

Sift

Uncertain

0.016

D;D

Sift4G

Uncertain

0.017

D;D

Polyphen

0.99

D;D

Vest4

0.21

MVP

0.52

MPC

0.030

ClinPred

0.11

GERP RS

4.3

PromoterAI

-0.017

Neutral

(source)

Varity_R

0.23

gMVP

0.27

Mutation Taster

=98/2

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over