21-37018065-A-C

Variant names:

• chr21-37018065-A-C
• rs1382995642
• NM_018962.3:c.431A>C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_018962.3(RIPPLY3):​c.431A>C​(p.Gln144Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,870 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RIPPLY3 NM_018962.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.97

Genes affected

RIPPLY3 (HGNC:3047): (ripply transcriptional repressor 3) Predicted to be involved in embryonic pattern specification and negative regulation of transcription by RNA polymerase II. Predicted to act upstream of or within negative regulation of cell population proliferation. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05570656).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RIPPLY3	NM_018962.3	c.431A>C	p.Gln144Pro	missense_variant	Exon 4 of 4	ENST00000329553.3	NP_061835.1
RIPPLY3	NM_001317768.2	c.179A>C	p.Gln60Pro	missense_variant	Exon 4 of 4		NP_001304697.1
RIPPLY3	NM_001317777.1	c.179A>C	p.Gln60Pro	missense_variant	Exon 3 of 3		NP_001304706.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RIPPLY3	ENST00000329553.3	c.431A>C	p.Gln144Pro	missense_variant	Exon 4 of 4	1	NM_018962.3	ENSP00000331734.2
RIPPLY3	ENST00000485272.5	n.411A>C		non_coding_transcript_exon_variant	Exon 4 of 4	1
RIPPLY3	ENST00000490393.1	n.291A>C		non_coding_transcript_exon_variant	Exon 3 of 3	1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251082 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135802

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461870 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727240

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 24, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.431A>C (p.Q144P) alteration is located in exon 4 (coding exon 4) of the RIPPLY3 gene. This alteration results from a A to C substitution at nucleotide position 431, causing the glutamine (Q) at amino acid position 144 to be replaced by a proline (P). 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	0.069
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	0.054
DANN	Benign	0.69
DEOGEN2	Benign	0.038	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.0059	N
LIST_S2	Benign	0.32	T
M_CAP	Benign	0.00070	T
MetaRNN	Benign	0.056	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.76	N
REVEL	Benign	0.0070
Sift	Benign	0.14	T
Sift4G	Benign	0.26	T
Polyphen		0.012	B
Vest4		0.090
MutPred		0.16		Gain of methylation at R143 (P = 0.0993);
MVP		0.085
MPC		0.13
ClinPred		0.060	T
GERP RS		-8.0
Varity_R		0.10
gMVP		0.038

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

LitVar

Other links and lift over

dbSNP: rs1382995642; hg19: chr21-38390365;