Variant 7-122702356-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_198085.2(RNF148):c.395A>G(p.Tyr132Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000114 in 1,613,836 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000099 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00012 ( 1 hom. )

Consequence

RNF148
NM_198085.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.802

Variant links:

Genes affected

RNF148 (HGNC:22411): (ring finger protein 148) Predicted to enable ubiquitin protein ligase activity. Predicted to be involved in ubiquitin-dependent protein catabolic process. Predicted to be integral component of membrane. Predicted to be active in Golgi apparatus; endoplasmic reticulum; and late endosome. [provided by Alliance of Genome Resources, Apr 2022]

RNF148 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 made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2797666).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RNF148	NM_198085.2 linkuse as main transcript	c.395A>G	p.Tyr132Cys	missense_variant	1/1	ENST00000434824.2	NP_932351.1
CADPS2	NM_017954.11 linkuse as main transcript	c.453+34599A>G		intron_variant		ENST00000449022.7	NP_060424.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RNF148	ENST00000434824.2 linkuse as main transcript	c.395A>G	p.Tyr132Cys	missense_variant	1/1		NM_198085.2	ENSP00000388207	P1
CADPS2	ENST00000449022.7 linkuse as main transcript	c.453+34599A>G		intron_variant		5	NM_017954.11	ENSP00000398481		Q86UW7-1

Frequencies

GnomAD3 genomes

AF:

0.0000986

AC:

AN:

152132

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000197

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:

0.000176

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000189

AC:

AN:

248964

Hom.:

AF XY:

0.000185

AC XY:

AN XY:

135062

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000927

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000975

Gnomad OTH exome

AF:

0.000497

GnomAD4 exome

AF:

0.000116

AC:

169

AN:

1461586

Hom.:

Cov.:

AF XY:

0.000110

AC XY:

AN XY:

727084

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000850

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000112

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.0000985

AC:

AN:

152250

Hom.:

Cov.:

AF XY:

0.0000940

AC XY:

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000176

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000114

Hom.:

Bravo

AF:

0.000155

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ExAC

AF:

0.000116

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 09, 2024

The c.395A>G (p.Y132C) alteration is located in exon 1 (coding exon 1) of the RNF148 gene. This alteration results from a A to G substitution at nucleotide position 395, causing the tyrosine (Y) at amino acid position 132 to be replaced by a cysteine (C). 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

Uncertain

0.38

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.46

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.10

Eigen

Uncertain

0.41

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Benign

0.74

LIST_S2

Benign

0.39

M_CAP

Benign

0.013

MetaRNN

Benign

0.28

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.1

MutationTaster

Benign

1.0

D;D;D;D;D;N

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-1.8

REVEL

Benign

0.20

Sift

Benign

0.16

Sift4G

Benign

0.17

Polyphen

0.98

Vest4

0.64

MVP

0.45

MPC

0.017

ClinPred

0.090

GERP RS

3.8

Varity_R

0.11

gMVP

0.20

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over