rs370933531

Positions:

chr6-83857238-T-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001009994.3(RIPPLY2):c.240-4T>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00111 in 1,483,028 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00072 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0011 ( 3 hom. )

Consequence

RIPPLY2
NM_001009994.3 splice_region, intron

Scores

Splicing: ADA: 0.1917

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3B:1O:1

Conservation

PhyloP100: 2.29

Variant links:

Genes affected

RIPPLY2 (HGNC:21390): (ripply transcriptional repressor 2) This gene encodes a nuclear protein that belongs to a novel family of proteins required for vertebrate somitogenesis. Members of this family have a tetrapeptide WRPW motif that is required for interaction with the transcriptional repressor Groucho and a carboxy-terminal Ripply homology domain/Bowline-DSCR-Ledgerline conserved region required for transcriptional repression. Null mutant mice die soon after birth and display defects in axial skeleton segmentation due to defective somitogenesis. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2016]

RIPPLY2 links:

RIPPLY2-CYB5R4 (HGNC:):

RIPPLY2-CYB5R4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.27).

BS2

High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RIPPLY2	NM_001009994.3 linkuse as main transcript	c.240-4T>G		splice_region_variant, intron_variant		ENST00000369689.6	NP_001009994.1	Q5TAB7-1

Ensembl

Gene	Transcript	HGVSc	Effect	#exon/exons	TSL	MANE	Protein	UniProt
RIPPLY2	ENST00000369689.6 linkuse as main transcript	c.240-4T>G	splice_region_variant, intron_variant		1	NM_001009994.3	ENSP00000358703.1	Q5TAB7-1
RIPPLY2	ENST00000369687.2 linkuse as main transcript	c.66-4T>G	splice_region_variant, intron_variant		2		ENSP00000358701.1	Q5TAB7-2
RIPPLY2	ENST00000635617.1 linkuse as main transcript	n.3649T>G	non_coding_transcript_exon_variant	1/1	6

Frequencies

GnomAD3 genomes

AF:

0.000717

AC:

109

AN:

152032

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000338

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000916

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:

0.00116

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.000644

AC:

118

AN:

183088

Hom.:

AF XY:

0.000572

AC XY:

AN XY:

101376

show subpopulations

Gnomad AFR exome

AF:

0.000411

Gnomad AMR exome

AF:

0.000319

Gnomad ASJ exome

AF:

0.000136

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00113

Gnomad OTH exome

AF:

0.000509

GnomAD4 exome

AF:

0.00115

AC:

1530

AN:

1330878

Hom.:

Cov.:

AF XY:

0.00110

AC XY:

723

AN XY:

657910

show subpopulations

Gnomad4 AFR exome

AF:

0.000144

Gnomad4 AMR exome

AF:

0.000484

Gnomad4 ASJ exome

AF:

0.0000446

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000398

Gnomad4 NFE exome

AF:

0.00140

Gnomad4 OTH exome

AF:

0.000831

GnomAD4 genome

AF:

0.000716

AC:

109

AN:

152150

Hom.:

Cov.:

AF XY:

0.000686

AC XY:

AN XY:

74388

show subpopulations

Gnomad4 AFR

AF:

0.000337

Gnomad4 AMR

AF:

0.000915

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00116

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.00106

Hom.:

Bravo

AF:

0.000816

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Benign:1Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Benign:1

Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	RIPPLY2: PM3:Strong, PP1:Strong, PM2:Supporting, PP4, BP4 -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -

Spondylocostal dysostosis 6, autosomal recessive

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 01, 2015

- -

RIPPLY2-related disorder

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 31, 2024

The RIPPLY2 c.240-4T>G variant is predicted to interfere with splicing. This variant is not predicted to significantly impact the splice acceptor site based on available splicing prediction programs; however, it is predicted to possibly create a SRp55 exonic splice enhancer site (Alamut Visual v2.11). This variant has been reported in the compound heterozygous state with a nonsense variant (p.Arg80*) in at least 4 individuals from two families with vertebral body malformations (McInerney-Leo et al. 2015. PubMed ID: 25343988; Wegler et al. 2021. PubMed ID: 33410135). The c.240-4T>G has also been reported in the homozygous state in an additional 4 individuals from 3 families with vertebral body malformations (Mokhateb-Rafii et al. 2018. PubMed ID: 30420309; see Table 1, Serey-Gaut et al. 2019. PubMed ID: 32212228). For a summary of all reported patients with c.240-4T>G and clinical features observed see Table 1 in Wegler et al. 2021. PubMed ID: 33410135. At PreventionGenetics, we have observed the c.240-4T>G variant in the homozygous state in two additional unrelated patients with vertebral anomalies (internal data). Functional studies via qPCR were attempted to observe a splicing defect; however, RIPPLY2 expression was unable to be detected in peripheral blood from healthy controls or patients likely due to Ripply2 expression being restricted to embryogenesis (McInerney-Leo et al. 2015. PubMed ID: 25343988). This variant is reported in 0.11% of alleles in individuals of European (non-Finnish) descent in gnomAD, but no homozygotes are observed. Although we suspect that this variant may be pathogenic, at this time the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Spondylocostal dysostosis 2, autosomal recessive

Other:1

not provided, no classification provided

literature only

GeneReviews

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.27

CADD

Benign

DANN

Benign

0.97

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.19

dbscSNV1_RF

Benign

0.36

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