rs9353143

Variant names:

• chr6-83853428-G-A
• rs9353143
• NM_001009994.3:c.12G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001009994.3(RIPPLY2):​c.12G>A​(p.Ala4Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.116 in 1,542,804 control chromosomes in the GnomAD database, including 21,502 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A4A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.24 (8046 hom., cov: 33)
  • Exomes 𝑓: 0.10 (13456 hom.)
• Consequence: RIPPLY2 NM_001009994.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.860
• Publications: 9 publications found

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 Gene-Disease associations (from GenCC):

• spondylocostal dysostosis 6, autosomal recessive

  Inheritance: AR, Unknown Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• autosomal recessive spondylocostal dysostosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000287705 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 6-83853428-G-A is Benign according to our data. Variant chr6-83853428-G-A is described in ClinVar as Benign. ClinVar VariationId is 1165051.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.86 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.564 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001009994.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RIPPLY2	NM_001009994.3	MANE Select	c.12G>A	p.Ala4Ala	synonymous	Exon 1 of 4	NP_001009994.1	Q5TAB7-1
	RIPPLY2	NM_001400900.1		c.12G>A	p.Ala4Ala	synonymous	Exon 1 of 3	NP_001387829.1
	RIPPLY2-CYB5R4	NR_174604.1		n.69G>A		non_coding_transcript_exon	Exon 1 of 18

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RIPPLY2	ENST00000369689.6	TSL:1 MANE Select	c.12G>A	p.Ala4Ala	synonymous	Exon 1 of 4	ENSP00000358703.1	Q5TAB7-1
	ENSG00000287705	ENST00000656981.1		n.740C>T		non_coding_transcript_exon	Exon 1 of 1
	RIPPLY2	ENST00000369687.2	TSL:2	c.-346G>A		upstream_gene	N/A	ENSP00000358701.1	Q5TAB7-2

Frequencies

GnomAD3 genomes AF: 0.244 AC: 37054 AN: 152098 Hom.: 8005 Cov.: 33

Gnomad AFR AF: 0.569

Gnomad AMI AF: 0.140

Gnomad AMR AF: 0.277

Gnomad ASJ AF: 0.0784

Gnomad EAS AF: 0.268

Gnomad SAS AF: 0.0689

Gnomad FIN AF: 0.114

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.0809

Gnomad OTH AF: 0.193

GnomAD2 exomes AF: 0.168 AC: 22998 AN: 136808 AF XY: 0.150

Gnomad AFR exome AF: 0.596

Gnomad AMR exome AF: 0.353

Gnomad ASJ exome AF: 0.0833

Gnomad EAS exome AF: 0.272

Gnomad FIN exome AF: 0.112

Gnomad NFE exome AF: 0.0780

Gnomad OTH exome AF: 0.126

GnomAD4 exome AF: 0.102 AC: 142325 AN: 1390588 Hom.: 13456 Cov.: 32 AF XY: 0.0992 AC XY: 68029 AN XY: 686082

African (AFR) AF: 0.589 AC: 18470 AN: 31342

American (AMR) AF: 0.337 AC: 11942 AN: 35488

Ashkenazi Jewish (ASJ) AF: 0.0777 AC: 1950 AN: 25102

East Asian (EAS) AF: 0.239 AC: 8529 AN: 35674

South Asian (SAS) AF: 0.0662 AC: 5236 AN: 79098

European-Finnish (FIN) AF: 0.113 AC: 4906 AN: 43252

Middle Eastern (MID) AF: 0.110 AC: 520 AN: 4746

European-Non Finnish (NFE) AF: 0.0773 AC: 83315 AN: 1078138

Other (OTH) AF: 0.129 AC: 7457 AN: 57748

GnomAD4 genome AF: 0.244 AC: 37163 AN: 152216 Hom.: 8046 Cov.: 33 AF XY: 0.243 AC XY: 18085 AN XY: 74426

African (AFR) AF: 0.570 AC: 23655 AN: 41522

American (AMR) AF: 0.277 AC: 4240 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0784 AC: 272 AN: 3470

East Asian (EAS) AF: 0.267 AC: 1374 AN: 5140

South Asian (SAS) AF: 0.0689 AC: 333 AN: 4830

European-Finnish (FIN) AF: 0.114 AC: 1211 AN: 10616

Middle Eastern (MID) AF: 0.105 AC: 31 AN: 294

European-Non Finnish (NFE) AF: 0.0809 AC: 5503 AN: 68022

Other (OTH) AF: 0.197 AC: 417 AN: 2114

Alfa AF: 0.139 Hom.: 1486

Bravo AF: 0.275

Asia WGS AF: 0.179 AC: 623 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Spondylocostal dysostosis 6, autosomal recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	3.4
DANN	Benign	0.88
PhyloP100		-0.86
PromoterAI		0.062	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs9353143; hg19: chr6-84563147; COSMIC: COSV63762512; COSMIC: COSV63762512;