chr4-153710411-T-C

Variant names:

• chr4-153710411-T-C
• rs1339
• NM_173662.4:c.945A>G

Variant summary

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

The NM_173662.4(RNF175):​c.945A>G​(p.Ile315Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.197 in 1,573,060 control chromosomes in the GnomAD database, including 32,494 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I315T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.16 (2506 hom., cov: 33)
  • Exomes 𝑓: 0.20 (29988 hom.)
• Consequence: RNF175 NM_173662.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.628
• Publications: 40 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=0.0014716387).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.292 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.945A>G	p.Ile315Met	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.945A>G	p.Ile315Met	missense	Exon 9 of 9	ENSP00000340979.4	Q8N4F7-1
	RNF175	ENST00000955649.1		c.849A>G	p.Ile283Met	missense	Exon 9 of 9	ENSP00000625708.1
	RNF175	ENST00000897861.1		c.843A>G	p.Ile281Met	missense	Exon 8 of 8	ENSP00000567920.1

Frequencies

GnomAD3 genomes AF: 0.161 AC: 24458 AN: 152124 Hom.: 2503 Cov.: 33

Gnomad AFR AF: 0.0429

Gnomad AMI AF: 0.136

Gnomad AMR AF: 0.137

Gnomad ASJ AF: 0.140

Gnomad EAS AF: 0.305

Gnomad SAS AF: 0.140

Gnomad FIN AF: 0.277

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.212

Gnomad OTH AF: 0.163

GnomAD2 exomes AF: 0.188 AC: 36417 AN: 194166 AF XY: 0.189

Gnomad AFR exome AF: 0.0421

Gnomad AMR exome AF: 0.0997

Gnomad ASJ exome AF: 0.146

Gnomad EAS exome AF: 0.302

Gnomad FIN exome AF: 0.279

Gnomad NFE exome AF: 0.215

Gnomad OTH exome AF: 0.184

GnomAD4 exome AF: 0.201 AC: 285202 AN: 1420818 Hom.: 29988 Cov.: 31 AF XY: 0.200 AC XY: 140703 AN XY: 702796

African (AFR) AF: 0.0361 AC: 1181 AN: 32738

American (AMR) AF: 0.104 AC: 4061 AN: 38944

Ashkenazi Jewish (ASJ) AF: 0.147 AC: 3728 AN: 25422

East Asian (EAS) AF: 0.270 AC: 10324 AN: 38290

South Asian (SAS) AF: 0.147 AC: 11923 AN: 80988

European-Finnish (FIN) AF: 0.274 AC: 14028 AN: 51144

Middle Eastern (MID) AF: 0.165 AC: 947 AN: 5736

European-Non Finnish (NFE) AF: 0.209 AC: 227309 AN: 1088592

Other (OTH) AF: 0.198 AC: 11701 AN: 58964

GnomAD4 genome AF: 0.161 AC: 24456 AN: 152242 Hom.: 2506 Cov.: 33 AF XY: 0.161 AC XY: 11995 AN XY: 74432

African (AFR) AF: 0.0428 AC: 1780 AN: 41576

American (AMR) AF: 0.137 AC: 2090 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.140 AC: 487 AN: 3470

East Asian (EAS) AF: 0.305 AC: 1579 AN: 5180

South Asian (SAS) AF: 0.141 AC: 678 AN: 4824

European-Finnish (FIN) AF: 0.277 AC: 2933 AN: 10586

Middle Eastern (MID) AF: 0.122 AC: 36 AN: 294

European-Non Finnish (NFE) AF: 0.212 AC: 14404 AN: 67998

Other (OTH) AF: 0.163 AC: 345 AN: 2112

Alfa AF: 0.191 Hom.: 8702

Bravo AF: 0.147

TwinsUK AF: 0.208 AC: 770

ALSPAC AF: 0.199 AC: 768

ESP6500AA AF: 0.0441 AC: 170

ESP6500EA AF: 0.207 AC: 1714

ExAC AF: 0.169 AC: 20179

Asia WGS AF: 0.205 AC: 712 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0028	T
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.35	N
LIST_S2	Uncertain	0.92	D
MetaRNN	Benign	0.0015	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.25	N
PhyloP100		-0.63
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.13
Sift	Benign	0.12	T
Sift4G	Benign	0.18	T
Polyphen		0.99	D
Vest4		0.20
MPC		0.27
ClinPred		0.068	T
GERP RS		-4.4
Varity_R		0.21
gMVP		0.53
Mutation Taster		=97/3	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: rs1339; hg19: chr4-154631563; COSMIC: COSV52605029; COSMIC: COSV52605029;