Genetic Variant RIPPLY1:p.Leu111Leu (chrX-106900874-G-A) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6BP7BS2

The NM_138382.3(RIPPLY1):c.331C>T(p.Leu111Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000168 in 1,209,306 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 66 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

Frequency

Genomes: 𝑓 0.00088 ( 0 hom., 30 hem., cov: 22)

Exomes 𝑓: 0.000095 ( 0 hom. 36 hem. )

Consequence

RIPPLY1
NM_138382.3 synonymous

Scores

Clinical Significance

Likely benign no assertion criteria provided B:1

Conservation

PhyloP100: 2.27

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.51).

BP6

Variant X-106900874-G-A is Benign according to our data. Variant chrX-106900874-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 3052211.Status of the report is no_assertion_criteria_provided, 0 stars.

BP7

Synonymous conserved (PhyloP=2.27 with no splicing effect.

BS2

High Hemizygotes in GnomAd4 at 30 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138382.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RIPPLY1	NM_138382.3	MANE Select	c.331C>T	p.Leu111Leu	synonymous	Exon 4 of 4	NP_612391.1	Q0D2K3-1
RIPPLY1	NM_001171706.2		c.190C>T	p.Leu64Leu	synonymous	Exon 2 of 2	NP_001165177.1	Q0D2K3-2
CLDN2	NM_001171092.1		c.-179+370G>A		intron	N/A	NP_001164563.1	P57739

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RIPPLY1	ENST00000276173.5	TSL:1 MANE Select	c.331C>T	p.Leu111Leu	synonymous	Exon 4 of 4	ENSP00000276173.4	Q0D2K3-1
RIPPLY1	ENST00000411805.1	TSL:1	c.190C>T	p.Leu64Leu	synonymous	Exon 2 of 2	ENSP00000400539.1	Q0D2K3-2
CLDN2	ENST00000541806.6	TSL:1	c.-179+370G>A		intron	N/A	ENSP00000441283.1	P57739

Frequencies

GnomAD3 genomes

AF:

0.000884

AC:

AN:

111979

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00293

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000566

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:

0.0000376

Gnomad OTH

AF:

0.000665

GnomAD2 exomes

AF:

0.000344

AC:

AN:

180392

AF XY:

0.000256

show subpopulations

Gnomad AFR exome

AF:

0.00414

Gnomad AMR exome

AF:

0.000330

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000248

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000948

AC:

104

AN:

1097274

Hom.:

Cov.:

AF XY:

0.0000992

AC XY:

AN XY:

362722

show subpopulations

African (AFR)

AF:

0.00239

AC:

AN:

26377

American (AMR)

AF:

0.000427

AC:

AN:

35165

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19356

East Asian (EAS)

AF:

0.0000331

AC:

AN:

30180

South Asian (SAS)

AF:

0.00

AC:

AN:

53888

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40502

Middle Eastern (MID)

AF:

0.000242

AC:

AN:

4135

European-Non Finnish (NFE)

AF:

0.0000143

AC:

AN:

841612

Other (OTH)

AF:

0.000261

AC:

AN:

46059

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

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:

0.000884

AC:

AN:

112032

Hom.:

Cov.:

AF XY:

0.000877

AC XY:

AN XY:

34222

show subpopulations

African (AFR)

AF:

0.00292

AC:

AN:

30832

American (AMR)

AF:

0.000565

AC:

AN:

10612

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2649

East Asian (EAS)

AF:

0.00

AC:

AN:

3559

South Asian (SAS)

AF:

0.00

AC:

AN:

2641

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6108

Middle Eastern (MID)

AF:

0.00

AC:

AN:

217

European-Non Finnish (NFE)

AF:

0.0000376

AC:

AN:

53209

Other (OTH)

AF:

0.000656

AC:

AN:

1524

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

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:

0.000391

Hom.:

Bravo

AF:

0.00114

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

RIPPLY1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.51

CADD

Benign

3.1

(source)

DANN

Benign

0.75

PhyloP100

2.3

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over