8-42850871-C-T

Position:

• chr8-42850871-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The ENST00000319104.7(RNF170):​c.523G>A​(p.Asp175Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00303 in 1,551,614 control chromosomes in the GnomAD database, including 52 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/13 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.010 (27 hom., cov: 31)
  • Exomes 𝑓: 0.0022 (25 hom.)
• Consequence: RNF170 ENST00000319104.7 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:3
• Conservation: PhyloP100: 0.0540

Genes affected

RNF170 (HGNC:25358): (ring finger protein 170) This gene encodes a RING domain-containing protein that resides in the endoplasmic reticulum (ER) membrane. This protein functions as an E3 ubiquitin ligase and mediates ubiquitination and processing of inositol 1,4,5-trisphosphate (IP3) receptors via the ER-associated protein degradation pathway. It is recruited to the activated IP3 receptors by the ERLIN1/ERLIN2 complex to which it is constitutively bound. Mutations in this gene are associated with autosomal dominant sensory ataxia. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jun 2012]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004593134).
• BP6: Variant 8-42850871-C-T is Benign according to our data. Variant chr8-42850871-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 1284768.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr8-42850871-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0104 (1583/152212) while in subpopulation AFR AF= 0.0314 (1305/41512). AF 95% confidence interval is 0.03. There are 27 homozygotes in gnomad4. There are 713 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 27 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RNF170	NM_001160224.2	c.523G>A	p.Asp175Asn	missense_variant	6/6		NP_001153696.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RNF170	ENST00000319104.7	c.523G>A	p.Asp175Asn	missense_variant	6/6	1		ENSP00000326138

Frequencies

GnomAD3 genomes AF: 0.0104 AC: 1585 AN: 152094 Hom.: 27 Cov.: 31

Gnomad AFR AF: 0.0316

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00668

Gnomad ASJ AF: 0.0159

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00134

Gnomad OTH AF: 0.0119

GnomAD3 exomes AF: 0.00404 AC: 622 AN: 154128 Hom.: 5 AF XY: 0.00351 AC XY: 287 AN XY: 81872

Gnomad AFR exome AF: 0.0305

Gnomad AMR exome AF: 0.00559

Gnomad ASJ exome AF: 0.0151

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000132

Gnomad FIN exome AF: 0.0000594

Gnomad NFE exome AF: 0.00143

Gnomad OTH exome AF: 0.00616

GnomAD4 exome AF: 0.00222 AC: 3112 AN: 1399402 Hom.: 25 Cov.: 31 AF XY: 0.00207 AC XY: 1430 AN XY: 690202

Gnomad4 AFR exome AF: 0.0327

Gnomad4 AMR exome AF: 0.00591

Gnomad4 ASJ exome AF: 0.0140

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000757

Gnomad4 FIN exome AF: 0.0000609

Gnomad4 NFE exome AF: 0.00108

Gnomad4 OTH exome AF: 0.00491

GnomAD4 genome AF: 0.0104 AC: 1583 AN: 152212 Hom.: 27 Cov.: 31 AF XY: 0.00958 AC XY: 713 AN XY: 74432

Gnomad4 AFR AF: 0.0314

Gnomad4 AMR AF: 0.00667

Gnomad4 ASJ AF: 0.0159

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.00134

Gnomad4 OTH AF: 0.0118

Alfa AF: 0.00366 Hom.: 4

Bravo AF: 0.0115

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.0246 AC: 34

ESP6500EA AF: 0.00157 AC: 5

ExAC AF: 0.00396 AC: 101

Asia WGS AF: 0.00173 AC: 7 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	1.0
DANN	Benign	0.95
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0071	N
LIST_S2	Benign	0.32	T
MetaRNN	Benign	0.0046	T
MetaSVM	Benign	-0.80	T
MutationTaster	Benign	1.0	N
PROVEAN	Benign	1.7	N
REVEL	Benign	0.079
Sift	Benign	0.44	T
Sift4G	Benign	0.86	T
Polyphen		0.023	B
Vest4		0.10
MVP		0.20
ClinPred		0.00024	T
GERP RS		0.11

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs73634689; hg19: chr8-42706014;