8-42856341-G-A

Position:

chr8-42856341-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP3_ModeratePP5_Very_Strong

The ENST00000527424.6(RNF170):c.595C>T(p.Arg199Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000139 in 1,439,842 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

RNF170
ENST00000527424.6 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 5.16

Variant links:

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]

RNF170 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM1

In a topological_domain Cytoplasmic (size 155) in uniprot entity RN170_HUMAN there are 7 pathogenic changes around while only 3 benign (70%) in ENST00000527424.6

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.845

PP5

Variant 8-42856341-G-A is Pathogenic according to our data. Variant chr8-42856341-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 31590.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RNF170	NM_030954.4 linkuse as main transcript	c.595C>T	p.Arg199Cys	missense_variant	7/7	ENST00000527424.6	NP_112216.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RNF170	ENST00000527424.6 linkuse as main transcript	c.595C>T	p.Arg199Cys	missense_variant	7/7	1	NM_030954.4	ENSP00000434797	P1	Q96K19-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000439

AC:

AN:

227970

Hom.:

AF XY:

0.00000809

AC XY:

AN XY:

123644

show subpopulations

Gnomad AFR exome

AF:

0.0000634

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000139

AC:

AN:

1439842

Hom.:

Cov.:

AF XY:

0.00000140

AC XY:

AN XY:

715804

show subpopulations

Gnomad4 AFR exome

AF:

0.0000314

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.04e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal dominant sensory ataxia 1

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	May 29, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jul 16, 2023	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with autosomal recessive spastic paraplegia 85 (MIM#619686). The mechanism of autosomal dominant sensory ataxia 1 (MIM#608984) is unclear, but toxic gain of function has been suggested (PMID: 21115467, PMID: 31636353). (I) 0108 - This gene is associated with both recessive and dominant disease (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (1 heterozygote, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (16 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been reported in at least four unrelated families with sensory ataxia, with or without vestibular areflexia or pyramidal involvement (PMID: 21115467, PMID: 32943585, PMID: 34469621). (SP) 0901 - This variant has strong evidence for segregation with disease (PMID: 21115467, PMID: 32943585, PMID: 34469621). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Spastic paraplegia 85, autosomal recessive

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Mar 20, 2023

Variant summary: RNF170 c.595C>T (p.Arg199Cys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.4e-06 in 227970 control chromosomes (gnomAD). c.595C>T has been reported in the literature in multiple individuals affected with Autosomal dominant sensory ataxia and the variant segregated with the disease (example: Valdamins_2011 and Cortese_2020). These data indicate that the variant is very likely to be associated with disease. One submitter (OMIM) have provided clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Pathogenic

0.45

BayesDel_noAF

Pathogenic

0.41

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.15

T;T;.

Eigen

Uncertain

0.65

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.95

D;.;D

M_CAP

Uncertain

0.16

MetaRNN

Pathogenic

0.84

D;D;D

MetaSVM

Uncertain

0.68

MutationAssessor

Pathogenic

2.9

M;M;.

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Pathogenic

0.79

PROVEAN

Pathogenic

-5.1

D;D;D

REVEL

Pathogenic

0.76

Sift

Pathogenic

0.0

D;D;T

Sift4G

Benign

0.067

T;T;T

Polyphen

0.99

D;D;.

Vest4

0.88

MutPred

0.51

Loss of solvent accessibility (P = 0.001);Loss of solvent accessibility (P = 0.001);.;

MVP

0.97

MPC

0.49

ClinPred

0.99

GERP RS

5.2

Varity_R

0.60

gMVP

0.91

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over