NM_001009994.3:c.240-4T>G

Variant names:

• chr6-83857238-T-G
• rs370933531
• NM_001009994.3:c.240-4T>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

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:3 B:1 O:1
• Conservation: PhyloP100: 2.29
• Publications: 5 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

RIPPLY2-CYB5R4 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.27).
• BS2: High Homozygotes in GnomAdExome4 at 3 AR,Unknown gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RIPPLY2	NM_001009994.3	MANE Select	c.240-4T>G		splice_region intron	N/A	NP_001009994.1
	RIPPLY2	NM_001400900.1		c.*3073T>G		3_prime_UTR	Exon 3 of 3	NP_001387829.1
	RIPPLY2-CYB5R4	NM_001400774.1		c.-28+3077T>G		intron	N/A	NP_001387703.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RIPPLY2	ENST00000369689.6	TSL:1 MANE Select	c.240-4T>G		splice_region intron	N/A	ENSP00000358703.1
	RIPPLY2	ENST00000369687.2	TSL:2	c.66-4T>G		splice_region intron	N/A	ENSP00000358701.1
	RIPPLY2	ENST00000635617.1	TSL:6	n.3649T>G		non_coding_transcript_exon	Exon 1 of 1

Frequencies

GnomAD3 genomes AF: 0.000717 AC: 109 AN: 152032 Hom.: 0 Cov.: 33

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

GnomAD2 exomes AF: 0.000644 AC: 118 AN: 183088 AF XY: 0.000572

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 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.: 3 Cov.: 27 AF XY: 0.00110 AC XY: 723 AN XY: 657910

African (AFR) AF: 0.000144 AC: 4 AN: 27690

American (AMR) AF: 0.000484 AC: 12 AN: 24778

Ashkenazi Jewish (ASJ) AF: 0.0000446 AC: 1 AN: 22422

East Asian (EAS) AF: 0.00 AC: 0 AN: 33958

South Asian (SAS) AF: 0.00 AC: 0 AN: 65518

European-Finnish (FIN) AF: 0.0000398 AC: 2 AN: 50198

Middle Eastern (MID) AF: 0.000209 AC: 1 AN: 4790

European-Non Finnish (NFE) AF: 0.00140 AC: 1465 AN: 1047394

Other (OTH) AF: 0.000831 AC: 45 AN: 54130

GnomAD4 genome AF: 0.000716 AC: 109 AN: 152150 Hom.: 0 Cov.: 33 AF XY: 0.000686 AC XY: 51 AN XY: 74388

African (AFR) AF: 0.000337 AC: 14 AN: 41568

American (AMR) AF: 0.000915 AC: 14 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00116 AC: 79 AN: 67888

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.00106 Hom.: 0

Bravo AF: 0.000816

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	-	1	not provided (2)
1	-	-	RIPPLY2-related disorder (1)
1	-	-	Spondylocostal dysostosis 6, autosomal recessive (1)
-	-	-	Spondylocostal dysostosis 2, autosomal recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.27
CADD	Benign	16
DANN	Benign	0.97
PhyloP100		2.3
Mutation Taster		=87/13	polymorphism

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

Other links and lift over

dbSNP: rs370933531; hg19: chr6-84566957;