Variant 4-153715537-A-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_173662.4(RNF175):c.756T>G(p.Cys252Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000876 in 1,594,708 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00072 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00089 ( 0 hom. )

Consequence

RNF175
NM_173662.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.281

Variant links:

Genes affected

RNF175 (HGNC:27735): (ring finger protein 175) Predicted to enable ubiquitin protein ligase activity. Predicted to be involved in ubiquitin-dependent ERAD pathway. Predicted to be integral component of membrane. Predicted to be active in Golgi membrane and endoplasmic reticulum membrane. [provided by Alliance of Genome Resources, Apr 2022]

RNF175 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.757

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RNF175	NM_173662.4 linkuse as main transcript	c.756T>G	p.Cys252Trp	missense_variant	7/9	ENST00000347063.9	NP_775933.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RNF175	ENST00000347063.9 linkuse as main transcript	c.756T>G	p.Cys252Trp	missense_variant	7/9	1	NM_173662.4	ENSP00000340979	P1	Q8N4F7-1
RNF175	ENST00000503694.5 linkuse as main transcript	c.*235T>G		3_prime_UTR_variant, NMD_transcript_variant	6/6	2		ENSP00000424430
RNF175	ENST00000513656.5 linkuse as main transcript	c.*503T>G		3_prime_UTR_variant, NMD_transcript_variant	6/7	3		ENSP00000421761

Frequencies

GnomAD3 genomes

AF:

0.000723

AC:

110

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00216

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00113

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000808

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000631

AC:

138

AN:

218858

Hom.:

AF XY:

0.000620

AC XY:

AN XY:

117760

show subpopulations

Gnomad AFR exome

AF:

0.000232

Gnomad AMR exome

AF:

0.000877

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000691

Gnomad NFE exome

AF:

0.000929

Gnomad OTH exome

AF:

0.000720

GnomAD4 exome

AF:

0.000892

AC:

1287

AN:

1442378

Hom.:

Cov.:

AF XY:

0.000892

AC XY:

638

AN XY:

715436

show subpopulations

Gnomad4 AFR exome

AF:

0.000181

Gnomad4 AMR exome

AF:

0.000799

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000629

Gnomad4 NFE exome

AF:

0.00106

Gnomad4 OTH exome

AF:

0.000769

GnomAD4 genome

AF:

0.000722

AC:

110

AN:

152330

Hom.:

Cov.:

AF XY:

0.000792

AC XY:

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.000216

Gnomad4 AMR

AF:

0.00216

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00113

Gnomad4 NFE

AF:

0.000808

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000773

Hom.:

Bravo

AF:

0.000763

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.000256

AC:

ESP6500EA

AF:

0.00157

AC:

ExAC

AF:

0.000340

AC:

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 16, 2023

The c.756T>G (p.C252W) alteration is located in exon 7 (coding exon 7) of the RNF175 gene. This alteration results from a T to G substitution at nucleotide position 756, causing the cysteine (C) at amino acid position 252 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

Pathogenic

0.90

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Pathogenic

0.48

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.37

Eigen

Benign

0.076

Eigen_PC

Benign

-0.23

FATHMM_MKL

Benign

0.071

LIST_S2

Uncertain

0.90

M_CAP

Pathogenic

0.63

MetaRNN

Pathogenic

0.76

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.6

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.58

PROVEAN

Pathogenic

-11

REVEL

Pathogenic

0.68

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.77

MVP

0.93

MPC

0.047

ClinPred

0.54

GERP RS

-0.27

Varity_R

0.96

gMVP

0.86

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

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