chr21-37017981-C-T

Variant names:

• chr21-37017981-C-T
• rs762912682
• NM_018962.3:c.347C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_018962.3(RIPPLY3):​c.347C>T​(p.Ser116Phe) 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. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S116C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RIPPLY3 NM_018962.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.34
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20671326).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018962.3. 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
	RIPPLY3	NM_018962.3	MANE Select	c.347C>T	p.Ser116Phe	missense	Exon 4 of 4	NP_061835.1	P57055-1
	RIPPLY3	NM_001317768.2		c.95C>T	p.Ser32Phe	missense	Exon 4 of 4	NP_001304697.1	P57055-2
	RIPPLY3	NM_001317777.1		c.95C>T	p.Ser32Phe	missense	Exon 3 of 3	NP_001304706.1	P57055-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RIPPLY3	ENST00000329553.3	TSL:1 MANE Select	c.347C>T	p.Ser116Phe	missense	Exon 4 of 4	ENSP00000331734.2	P57055-1
	RIPPLY3	ENST00000485272.5	TSL:1	n.327C>T		non_coding_transcript_exon	Exon 4 of 4
	RIPPLY3	ENST00000490393.1	TSL:1	n.207C>T		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461870 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727238

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112004

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.013	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.49	T
Eigen	Benign	0.10
Eigen_PC	Benign	-0.089
FATHMM_MKL	Benign	0.063	N
LIST_S2	Benign	0.41	T
M_CAP	Benign	0.0015	T
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.75	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		1.3
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.12
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0090	D
Polyphen		1.0	D
Vest4		0.15
MutPred		0.17		Loss of phosphorylation at S116 (P = 0.0088)
MVP		0.13
MPC		0.12
ClinPred		0.81	D
GERP RS		4.8
Varity_R		0.32
gMVP		0.046
Mutation Taster		=88/12	polymorphism

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

Other links and lift over

dbSNP: rs762912682; hg19: chr21-38390281;