Genetic Variant RNF175:p.Leu307Phe (chr4-153710435-C-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_173662.4(RNF175):c.921G>C(p.Leu307Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.185 in 1,594,636 control chromosomes in the GnomAD database, including 30,058 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.15 ( 2185 hom., cov: 32)

Exomes 𝑓: 0.19 ( 27873 hom. )

Consequence

RNF175
NM_173662.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.30

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:

TLR2 (HGNC:11848): (toll like receptor 2) The protein encoded by this gene is a member of the Toll-like receptor (TLR) family which plays a fundamental role in pathogen recognition and activation of innate immunity. TLRs are highly conserved from Drosophila to humans and share structural and functional similarities. This protein is a cell-surface protein that can form heterodimers with other TLR family members to recognize conserved molecules derived from microorganisms known as pathogen-associated molecular patterns (PAMPs). Activation of TLRs by PAMPs leads to an up-regulation of signaling pathways to modulate the host's inflammatory response. This gene is also thought to promote apoptosis in response to bacterial lipoproteins. This gene has been implicated in the pathogenesis of several autoimmune diseases. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

TLR2 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.001729101).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.209 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RNF175	NM_173662.4 link	c.921G>C	p.Leu307Phe	missense_variant	Exon 9 of 9	ENST00000347063.9	NP_775933.2	Q8N4F7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RNF175	ENST00000347063.9 link	c.921G>C	p.Leu307Phe	missense_variant	Exon 9 of 9	1	NM_173662.4	ENSP00000340979.4		Q8N4F7-1

Frequencies

GnomAD3 genomes

AF:

0.147

AC:

22357

AN:

152058

Hom.:

2186

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0335

Gnomad AMI

AF:

0.152

Gnomad AMR

AF:

0.150

Gnomad ASJ

AF:

0.176

Gnomad EAS

AF:

0.00269

Gnomad SAS

AF:

0.121

Gnomad FIN

AF:

0.249

Gnomad MID

AF:

0.101

Gnomad NFE

AF:

0.212

Gnomad OTH

AF:

0.134

GnomAD3 exomes

AF:

0.162

AC:

36259

AN:

223506

Hom.:

3507

AF XY:

0.164

AC XY:

19674

AN XY:

120036

show subpopulations

Gnomad AFR exome

AF:

0.0301

Gnomad AMR exome

AF:

0.160

Gnomad ASJ exome

AF:

0.156

Gnomad EAS exome

AF:

0.00209

Gnomad SAS exome

AF:

0.120

Gnomad FIN exome

AF:

0.233

Gnomad NFE exome

AF:

0.205

Gnomad OTH exome

AF:

0.174

GnomAD4 exome

AF:

0.189

AC:

272673

AN:

1442460

Hom.:

27873

Cov.:

AF XY:

0.188

AC XY:

134608

AN XY:

715506

show subpopulations

Gnomad4 AFR exome

AF:

0.0289

Gnomad4 AMR exome

AF:

0.158

Gnomad4 ASJ exome

AF:

0.163

Gnomad4 EAS exome

AF:

0.00145

Gnomad4 SAS exome

AF:

0.120

Gnomad4 FIN exome

AF:

0.233

Gnomad4 NFE exome

AF:

0.207

Gnomad4 OTH exome

AF:

0.168

GnomAD4 genome

AF:

0.147

AC:

22351

AN:

152176

Hom.:

2185

Cov.:

AF XY:

0.148

AC XY:

10991

AN XY:

74394

show subpopulations

Gnomad4 AFR

AF:

0.0334

Gnomad4 AMR

AF:

0.150

Gnomad4 ASJ

AF:

0.176

Gnomad4 EAS

AF:

0.00270

Gnomad4 SAS

AF:

0.122

Gnomad4 FIN

AF:

0.249

Gnomad4 NFE

AF:

0.212

Gnomad4 OTH

AF:

0.132

Alfa

AF:

0.189

Hom.:

2375

Bravo

AF:

0.132

TwinsUK

AF:

0.209

AC:

776

ALSPAC

AF:

0.217

AC:

836

ESP6500AA

AF:

0.0369

AC:

142

ESP6500EA

AF:

0.199

AC:

1648

ExAC

AF:

0.150

AC:

18043

Asia WGS

AF:

0.0560

AC:

200

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.51

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.031

Eigen

Uncertain

0.33

Eigen_PC

Uncertain

0.25

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.85

MetaRNN

Benign

0.0017

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.8

PrimateAI

Benign

0.42

PROVEAN

Benign

-2.3

REVEL

Benign

0.23

Sift

Benign

0.12

Sift4G

Benign

0.18

Polyphen

0.98

Vest4

0.23

MutPred

0.50

Gain of helix (P = 0.0854);

MPC

0.27

ClinPred

0.015

GERP RS

2.5

Varity_R

0.13

gMVP

0.60

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over