21-37006800-C-T

Variant names:

• chr21-37006800-C-T
• rs925641455
• NM_018962.3:c.28C>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.28C>T​(p.Arg10Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 152,060 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. R10G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RIPPLY3 NM_018962.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.428
• 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=0.17077044).

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.28C>T	p.Arg10Trp	missense	Exon 1 of 4	NP_061835.1	P57055-1
	RIPPLY3	NM_001317768.2		c.-149+567C>T		intron	N/A	NP_001304697.1	P57055-2
	RIPPLY3	NM_001317777.1		c.-81+567C>T		intron	N/A	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.28C>T	p.Arg10Trp	missense	Exon 1 of 4	ENSP00000331734.2	P57055-1
	RIPPLY3	ENST00000485272.5	TSL:1	n.84+567C>T		intron	N/A
	RIPPLY3	ENST00000490393.1	TSL:1	n.32+567C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152060 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1080712 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 512276

African (AFR) AF: 0.00 AC: 0 AN: 22600

American (AMR) AF: 0.00 AC: 0 AN: 8246

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14054

East Asian (EAS) AF: 0.00 AC: 0 AN: 26060

South Asian (SAS) AF: 0.00 AC: 0 AN: 21338

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 21336

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2894

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 920878

Other (OTH) AF: 0.00 AC: 0 AN: 43306

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152060 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74282

African (AFR) AF: 0.00 AC: 0 AN: 41440

American (AMR) AF: 0.00 AC: 0 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10576

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67994

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.065
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.60	T
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.81	L
PhyloP100		0.43
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.046
Sift	Uncertain	0.019	D
Sift4G	Uncertain	0.037	D
Polyphen		0.99	D
Vest4		0.080
MutPred		0.27		Loss of methylation at R10 (P = 0.0287)
MVP		0.23
MPC		0.093
ClinPred		0.64	D
GERP RS		2.5
PromoterAI		-0.30	Neutral
Varity_R		0.10
gMVP		0.24
Mutation Taster		=92/8	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: rs925641455; hg19: chr21-38379100;