Genetic Variant RNF133:p.Ala343Thr (chr7-122697892-C-T) – 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_139175.2(RNF133):c.1027G>A(p.Ala343Thr) 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. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

RNF133
NM_139175.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.751

Publications

0 publications found

Variant links:

Genes affected

RNF133 (HGNC:21154): (ring finger protein 133) The protein encoded by this gene contains a RING finger domain, a motif present in a variety of functionally distinct proteins and known to be involved in protein-protein and protein-DNA interactions. This gene has no intron. [provided by RefSeq, Jul 2008]

RNF133 links:

CADPS2 (HGNC:16018): (calcium dependent secretion activator 2) This gene encodes a member of the calcium-dependent activator of secretion (CAPS) protein family, which are calcium binding proteins that regulate the exocytosis of synaptic and dense-core vesicles in neurons and neuroendocrine cells. Mutations in this gene may contribute to autism susceptibility. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2009]

CADPS2 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=0.052514106).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_139175.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RNF133	NM_139175.2	MANE Select	c.1027G>A	p.Ala343Thr	missense	Exon 1 of 1	NP_631914.1	Q8WVZ7
CADPS2	NM_017954.11	MANE Select	c.454-34323G>A		intron	N/A	NP_060424.9
CADPS2	NM_001363389.2		c.454-34323G>A		intron	N/A	NP_001350318.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RNF133	ENST00000340112.3	TSL:6 MANE Select	c.1027G>A	p.Ala343Thr	missense	Exon 1 of 1	ENSP00000344489.2	Q8WVZ7
CADPS2	ENST00000449022.7	TSL:5 MANE Select	c.454-34323G>A		intron	N/A	ENSP00000398481.2	Q86UW7-1
CADPS2	ENST00000412584.6	TSL:1	c.454-34323G>A		intron	N/A	ENSP00000400401.2	Q86UW7-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000796

AC:

AN:

251128

AF XY:

0.00000737

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1461216

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726944

African (AFR)

AF:

0.00

AC:

AN:

33454

American (AMR)

AF:

0.00

AC:

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26114

East Asian (EAS)

AF:

0.00

AC:

AN:

39686

South Asian (SAS)

AF:

0.00

AC:

AN:

86242

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53406

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111474

Other (OTH)

AF:

0.00

AC:

AN:

60364

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.84

CADD

Benign

9.0

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.0067

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.10

LIST_S2

Benign

0.38

M_CAP

Benign

0.0061

MetaRNN

Benign

0.053

MetaSVM

Benign

-0.95

MutationAssessor

Benign

1.6

PhyloP100

-0.75

PrimateAI

Benign

0.22

PROVEAN

Benign

-0.46

REVEL

Benign

0.0070

Sift

Uncertain

0.021

Sift4G

Benign

0.15

Polyphen

0.012

Vest4

0.078

MutPred

0.18

Loss of sheet (P = 0.0228)

MVP

0.17

MPC

0.021

ClinPred

0.039

GERP RS

-0.67

Varity_R

0.041

gMVP

0.065

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over