Genetic Variant NM_018962.3:c.508T>G (chr21-37018142-T-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_018962.3(RIPPLY3):c.508T>G(p.Trp170Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000233 in 1,461,704 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 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. W170C) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

RIPPLY3
NM_018962.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -3.15

Publications

0 publications found

Variant links:

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]

RIPPLY3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.032948345).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RIPPLY3	NM_018962.3 link	c.508T>G	p.Trp170Gly	missense_variant	Exon 4 of 4	ENST00000329553.3	NP_061835.1	P57055-1
RIPPLY3	NM_001317768.2 link	c.256T>G	p.Trp86Gly	missense_variant	Exon 4 of 4		NP_001304697.1	P57055-2
RIPPLY3	NM_001317777.1 link	c.256T>G	p.Trp86Gly	missense_variant	Exon 3 of 3		NP_001304706.1	P57055-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
RIPPLY3	ENST00000329553.3 link	c.508T>G	p.Trp170Gly	missense_variant	Exon 4 of 4	1	NM_018962.3	ENSP00000331734.2	P57055-1
RIPPLY3	ENST00000485272.5 link	n.488T>G		non_coding_transcript_exon_variant	Exon 4 of 4	1
RIPPLY3	ENST00000490393.1 link	n.368T>G		non_coding_transcript_exon_variant	Exon 3 of 3	1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.0000233

AC:

AN:

1461704

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

727164

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53280

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000288

AC:

AN:

1111974

Other (OTH)

AF:

0.0000331

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.058

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.73

CADD

Benign

0.034

(source)

DANN

Benign

0.34

DEOGEN2

Benign

0.033

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.0048

LIST_S2

Benign

0.13

M_CAP

Benign

0.0026

MetaRNN

Benign

0.033

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.20

PhyloP100

-3.1

PrimateAI

Benign

0.27

PROVEAN

Benign

0.26

REVEL

Benign

0.0070

Sift

Benign

0.88

Sift4G

Benign

0.35

Polyphen

0.0

Vest4

0.072

MutPred

0.26

Loss of MoRF binding (P = 0.1106);

MVP

0.061

MPC

0.18

ClinPred

0.030

GERP RS

-7.7

Varity_R

0.056

gMVP

0.043

Mutation Taster

=95/5

polymorphism

(source)

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

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NM_018962.3:c.508T>G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over