4-153712582-G-C

Variant names:

• chr4-153712582-G-C
• rs2289318
• NM_173662.4:c.765-6C>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.765-6C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.203 in 1,594,806 control chromosomes in the GnomAD database, including 33,407 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.21 (3445 hom., cov: 32)
  • Exomes 𝑓: 0.20 (29962 hom.)
• Consequence: RNF175 NM_173662.4 splice_region, intron
• Scores: Splicing: ADA: 0.5802
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.56
• Publications: 23 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]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.218 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.765-6C>G		splice_region intron	N/A	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.765-6C>G		splice_region intron	N/A	ENSP00000340979.4	Q8N4F7-1
	RNF175	ENST00000955649.1		c.669-6C>G		splice_region intron	N/A	ENSP00000625708.1
	RNF175	ENST00000897861.1		c.765-2093C>G		intron	N/A	ENSP00000567920.1

Frequencies

GnomAD3 genomes AF: 0.213 AC: 32390 AN: 152006 Hom.: 3441 Cov.: 32

Gnomad AFR AF: 0.215

Gnomad AMI AF: 0.136

Gnomad AMR AF: 0.225

Gnomad ASJ AF: 0.216

Gnomad EAS AF: 0.229

Gnomad SAS AF: 0.195

Gnomad FIN AF: 0.246

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.206

Gnomad OTH AF: 0.196

GnomAD2 exomes AF: 0.208 AC: 50631 AN: 243170 AF XY: 0.207

Gnomad AFR exome AF: 0.213

Gnomad AMR exome AF: 0.213

Gnomad ASJ exome AF: 0.206

Gnomad EAS exome AF: 0.226

Gnomad FIN exome AF: 0.235

Gnomad NFE exome AF: 0.203

Gnomad OTH exome AF: 0.211

GnomAD4 exome AF: 0.201 AC: 290661 AN: 1442680 Hom.: 29962 Cov.: 27 AF XY: 0.202 AC XY: 144865 AN XY: 718362

African (AFR) AF: 0.210 AC: 6951 AN: 33170

American (AMR) AF: 0.210 AC: 9273 AN: 44204

Ashkenazi Jewish (ASJ) AF: 0.207 AC: 5366 AN: 25960

East Asian (EAS) AF: 0.248 AC: 9811 AN: 39602

South Asian (SAS) AF: 0.190 AC: 16207 AN: 85222

European-Finnish (FIN) AF: 0.234 AC: 12438 AN: 53198

Middle Eastern (MID) AF: 0.145 AC: 831 AN: 5742

European-Non Finnish (NFE) AF: 0.199 AC: 217887 AN: 1095806

Other (OTH) AF: 0.199 AC: 11897 AN: 59776

GnomAD4 genome AF: 0.213 AC: 32404 AN: 152126 Hom.: 3445 Cov.: 32 AF XY: 0.215 AC XY: 15992 AN XY: 74356

African (AFR) AF: 0.215 AC: 8918 AN: 41506

American (AMR) AF: 0.225 AC: 3432 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.216 AC: 749 AN: 3472

East Asian (EAS) AF: 0.229 AC: 1183 AN: 5174

South Asian (SAS) AF: 0.196 AC: 943 AN: 4822

European-Finnish (FIN) AF: 0.246 AC: 2602 AN: 10576

Middle Eastern (MID) AF: 0.109 AC: 32 AN: 294

European-Non Finnish (NFE) AF: 0.206 AC: 14010 AN: 67980

Other (OTH) AF: 0.195 AC: 411 AN: 2104

Alfa AF: 0.207 Hom.: 1083

Bravo AF: 0.206

Asia WGS AF: 0.179 AC: 628 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	12
DANN	Benign	0.76
PhyloP100		2.6
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.58
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: rs2289318; hg19: chr4-154633734; COSMIC: COSV56840674; COSMIC: COSV56840674;