rs587780441

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 1P and 5B. PP5BP4BS2

The NM_030954.4(RNF170):c.640A>G(p.Ile214Val) variant causes a missense change. The variant allele was found at a frequency of 0.000125 in 1,586,676 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00013 ( 5 hom. )

Consequence

RNF170
NM_030954.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:2

Conservation

PhyloP100: 4.50

Publications

2 publications found

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 Gene-Disease associations (from GenCC):

autosomal dominant sensory ataxia 1
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
spastic paraplegia 85, autosomal recessive
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

RNF170 links:

ENSG00000286837 (HGNC:):

ENSG00000286837 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

PP5

Variant 8-42856296-T-C is Pathogenic according to our data. Variant chr8-42856296-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 130158.

BP4

Computational evidence support a benign effect (MetaRNN=0.014598697). . Strength limited to SUPPORTING due to the PP5.

BS2

High Homozygotes in GnomAdExome4 at 5 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_030954.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
RNF170	NM_030954.4	MANE Select	c.640A>G	p.Ile214Val	missense	Exon 7 of 7	NP_112216.3
RNF170	NM_001160223.2		c.640A>G	p.Ile214Val	missense	Exon 7 of 7	NP_001153695.1
RNF170	NM_001160225.2		c.388A>G	p.Ile130Val	missense	Exon 7 of 7	NP_001153697.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
RNF170	ENST00000527424.6	TSL:1 MANE Select	c.640A>G	p.Ile214Val	missense	Exon 7 of 7	ENSP00000434797.1
RNF170	ENST00000534961.5	TSL:1	c.640A>G	p.Ile214Val	missense	Exon 7 of 7	ENSP00000445725.1
RNF170	ENST00000526349.5	TSL:1	c.388A>G	p.Ile130Val	missense	Exon 7 of 7	ENSP00000435782.1

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152148

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000231

AC:

AN:

225378

AF XY:

0.000368

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 FIN exome

AF:

0.0000973

Gnomad NFE exome

AF:

0.0000563

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000130

AC:

187

AN:

1434410

Hom.:

Cov.:

AF XY:

0.000184

AC XY:

131

AN XY:

712576

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31562

American (AMR)

AF:

0.0000273

AC:

AN:

36664

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24688

East Asian (EAS)

AF:

0.00

AC:

AN:

39556

South Asian (SAS)

AF:

0.00181

AC:

146

AN:

80692

European-Finnish (FIN)

AF:

0.0000952

AC:

AN:

52510

Middle Eastern (MID)

AF:

0.000358

AC:

AN:

5588

European-Non Finnish (NFE)

AF:

0.0000109

AC:

AN:

1104054

Other (OTH)

AF:

0.000355

AC:

AN:

59096

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000722

AC:

AN:

152266

Hom.:

Cov.:

AF XY:

0.000107

AC XY:

AN XY:

74450

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41558

American (AMR)

AF:

0.00

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00207

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68016

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.570

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000139

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.000231

AC:

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Autosomal dominant sensory ataxia 1 (2)

not specified (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.34

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.013

Eigen

Benign

-0.19

Eigen_PC

Benign

0.046

FATHMM_MKL

Uncertain

0.79

LIST_S2

Benign

0.80

M_CAP

Benign

0.011

MetaRNN

Benign

0.015

MetaSVM

Benign

-0.61

MutationAssessor

Benign

0.45

PhyloP100

4.5

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-0.33

REVEL

Benign

0.22

Sift

Benign

0.31

Sift4G

Benign

0.52

Polyphen

0.0010

Vest4

0.052

MutPred

0.56

Loss of loop (P = 0.2237)

MVP

0.23

MPC

0.29

ClinPred

0.83

GERP RS

4.8

Varity_R

0.043

gMVP

0.64

Mutation Taster

=76/24

disease causing (ClinVar)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over