chr4-153710435-C-G

Variant names:

• chr4-153710435-C-G
• rs1337
• NM_173662.4:c.921G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

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. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.15 (2185 hom., cov: 32)
  • Exomes 𝑓: 0.19 (27873 hom.)
• Consequence: RNF175 NM_173662.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.30
• Publications: 32 publications found

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]

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]

ACMG classification

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_173662.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RNF175	NM_173662.4	MANE Select	c.921G>C	p.Leu307Phe	missense	Exon 9 of 9	NP_775933.2	Q8N4F7-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RNF175	ENST00000347063.9	TSL:1 MANE Select	c.921G>C	p.Leu307Phe	missense	Exon 9 of 9	ENSP00000340979.4	Q8N4F7-1
	RNF175	ENST00000955649.1		c.825G>C	p.Leu275Phe	missense	Exon 9 of 9	ENSP00000625708.1
	RNF175	ENST00000897861.1		c.819G>C	p.Leu273Phe	missense	Exon 8 of 8	ENSP00000567920.1

Frequencies

GnomAD3 genomes AF: 0.147 AC: 22357 AN: 152058 Hom.: 2186 Cov.: 32

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

GnomAD2 exomes AF: 0.162 AC: 36259 AN: 223506 AF XY: 0.164

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 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.: 31 AF XY: 0.188 AC XY: 134608 AN XY: 715506

African (AFR) AF: 0.0289 AC: 960 AN: 33214

American (AMR) AF: 0.158 AC: 6644 AN: 42184

Ashkenazi Jewish (ASJ) AF: 0.163 AC: 4186 AN: 25678

East Asian (EAS) AF: 0.00145 AC: 57 AN: 39372

South Asian (SAS) AF: 0.120 AC: 9982 AN: 82940

European-Finnish (FIN) AF: 0.233 AC: 12198 AN: 52456

Middle Eastern (MID) AF: 0.111 AC: 638 AN: 5756

European-Non Finnish (NFE) AF: 0.207 AC: 227988 AN: 1101130

Other (OTH) AF: 0.168 AC: 10020 AN: 59730

GnomAD4 genome AF: 0.147 AC: 22351 AN: 152176 Hom.: 2185 Cov.: 32 AF XY: 0.148 AC XY: 10991 AN XY: 74394

African (AFR) AF: 0.0334 AC: 1387 AN: 41528

American (AMR) AF: 0.150 AC: 2295 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.176 AC: 609 AN: 3468

East Asian (EAS) AF: 0.00270 AC: 14 AN: 5188

South Asian (SAS) AF: 0.122 AC: 587 AN: 4828

European-Finnish (FIN) AF: 0.249 AC: 2628 AN: 10572

Middle Eastern (MID) AF: 0.102 AC: 30 AN: 294

European-Non Finnish (NFE) AF: 0.212 AC: 14382 AN: 67984

Other (OTH) AF: 0.132 AC: 280 AN: 2114

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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.031	T
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.85	D
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L
PhyloP100		1.3
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.23
Sift	Benign	0.12	T
Sift4G	Benign	0.18	T
Polyphen		0.98	D
Vest4		0.23
MutPred		0.50		Gain of helix (P = 0.0854)
MPC		0.27
ClinPred		0.015	T
GERP RS		2.5
Varity_R		0.13
gMVP		0.60
Mutation Taster		=92/8	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1337; hg19: chr4-154631587; COSMIC: COSV52608465; COSMIC: COSV52608465;