8-42870022-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5

The NM_030954.4(RNF170):ā€‹c.304T>Cā€‹(p.Cys102Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,334 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 0.0000014 ( 0 hom. )

Consequence

RNF170
NM_030954.4 missense

Scores

15
3
1

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:1

Conservation

PhyloP100: 8.04
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.964
PP5
Variant 8-42870022-A-G is Pathogenic according to our data. Variant chr8-42870022-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 638435.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}. Variant chr8-42870022-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RNF170NM_030954.4 linkc.304T>C p.Cys102Arg missense_variant Exon 4 of 7 ENST00000527424.6 NP_112216.3 Q96K19-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
RNF170ENST00000527424.6 linkc.304T>C p.Cys102Arg missense_variant Exon 4 of 7 1 NM_030954.4 ENSP00000434797.1 Q96K19-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251336
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135836
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1461334
Hom.:
0
Cov.:
31
AF XY:
0.00000275
AC XY:
2
AN XY:
727022
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.00e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:3Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Spastic paraplegia 85, autosomal recessive Pathogenic:2
Mar 22, 2022
3billion, Medical Genetics
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Same or different nucleotide change resulting in same amino acid change has been previously reported to be associated with RNF170 related disorder (PMID:31636353). The variant has been reported to co-segregate with the disease in at least 3 similarly affected relatives/individuals in the same family or similarly affected unrelated family (PMID: 31636353). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.959>=0.6, 3CNET: 0.975>=0.75). The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000004). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. -

Jan 05, 2022
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Spastic paraplegia Pathogenic:1
Oct 21, 2019
Yale Center for Mendelian Genomics, Yale University
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Autosomal dominant sensory ataxia 1 Uncertain:1
Apr 27, 2019
Genomic Research Center, Shahid Beheshti University of Medical Sciences
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.51
D
BayesDel_noAF
Pathogenic
0.60
CADD
Pathogenic
30
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.79
.;D;D;.;.;.
Eigen
Pathogenic
0.97
Eigen_PC
Pathogenic
0.85
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Pathogenic
0.99
D;D;.;D;D;D
M_CAP
Pathogenic
0.76
D
MetaRNN
Pathogenic
0.96
D;D;D;D;D;D
MetaSVM
Pathogenic
0.93
D
MutationAssessor
Pathogenic
4.1
H;H;H;.;H;.
PrimateAI
Uncertain
0.78
T
PROVEAN
Pathogenic
-12
D;D;D;D;.;D
REVEL
Pathogenic
0.96
Sift
Pathogenic
0.0
D;D;D;D;.;D
Sift4G
Pathogenic
0.0
D;D;D;D;D;.
Polyphen
1.0
D;D;D;.;.;.
Vest4
0.98
MutPred
0.78
Gain of disorder (P = 0.0417);Gain of disorder (P = 0.0417);Gain of disorder (P = 0.0417);.;Gain of disorder (P = 0.0417);Gain of disorder (P = 0.0417);
MVP
0.91
MPC
1.5
ClinPred
1.0
D
GERP RS
5.6
Varity_R
0.99
gMVP
0.98

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.

Other links and lift over

dbSNP: rs1183403793; hg19: chr8-42725165; API