21-37018112-G-T

Variant names:

• chr21-37018112-G-T
• NM_018962.3:c.478G>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_018962.3(RIPPLY3):​c.478G>T​(p.Gly160Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/20 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)
• Consequence: RIPPLY3 NM_018962.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.182

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12066734).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RIPPLY3	NM_018962.3	c.478G>T	p.Gly160Trp	missense_variant	Exon 4 of 4	ENST00000329553.3	NP_061835.1
RIPPLY3	NM_001317768.2	c.226G>T	p.Gly76Trp	missense_variant	Exon 4 of 4		NP_001304697.1
RIPPLY3	NM_001317777.1	c.226G>T	p.Gly76Trp	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.478G>T	p.Gly160Trp	missense_variant	Exon 4 of 4	1	NM_018962.3	ENSP00000331734.2
RIPPLY3	ENST00000485272.5	n.458G>T		non_coding_transcript_exon_variant	Exon 4 of 4	1
RIPPLY3	ENST00000490393.1	n.338G>T		non_coding_transcript_exon_variant	Exon 3 of 3	1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 12, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.478G>T (p.G160W) alteration is located in exon 4 (coding exon 4) of the RIPPLY3 gene. This alteration results from a G to T substitution at nucleotide position 478, causing the glycine (G) at amino acid position 160 to be replaced by a tryptophan (W). 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	0.13
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	16
DANN	Uncertain	0.98
DEOGEN2	Benign	0.093	T
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.029	N
LIST_S2	Benign	0.30	T
M_CAP	Benign	0.0025	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.77	N
REVEL	Benign	0.070
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.21
MutPred		0.18		Gain of sheet (P = 0.0149);
MVP		0.040
MPC		0.41
ClinPred		0.41	T
GERP RS		-1.2
Varity_R		0.10
gMVP		0.060

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr21-38390412;