8-42865438-C-T

Position:

chr8-42865438-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_030954.4(RNF170):c.374G>A(p.Ser125Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00383 in 1,613,544 control chromosomes in the GnomAD database, including 48 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0037 ( 5 hom., cov: 32)

Exomes 𝑓: 0.0038 ( 43 hom. )

Consequence

RNF170
NM_030954.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 1.83

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0070908964).

BP6

Variant 8-42865438-C-T is Benign according to our data. Variant chr8-42865438-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 522306.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-42865438-C-T is described in Lovd as [Benign]. Variant chr8-42865438-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00367 (558/152190) while in subpopulation SAS AF= 0.00995 (48/4824). AF 95% confidence interval is 0.00771. There are 5 homozygotes in gnomad4. There are 291 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 5 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RNF170	NM_030954.4 linkuse as main transcript	c.374G>A	p.Ser125Asn	missense_variant	5/7	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.374G>A	p.Ser125Asn	missense_variant	5/7	1	NM_030954.4	ENSP00000434797	P1	Q96K19-1

Frequencies

GnomAD3 genomes

AF:

0.00368

AC:

559

AN:

152072

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000507

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00858

Gnomad ASJ

AF:

0.0135

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0101

Gnomad FIN

AF:

0.00293

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00387

Gnomad OTH

AF:

0.00718

GnomAD3 exomes

AF:

0.00476

AC:

1196

AN:

251134

Hom.:

AF XY:

0.00536

AC XY:

728

AN XY:

135798

show subpopulations

Gnomad AFR exome

AF:

0.000370

Gnomad AMR exome

AF:

0.00359

Gnomad ASJ exome

AF:

0.0163

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0102

Gnomad FIN exome

AF:

0.00185

Gnomad NFE exome

AF:

0.00457

Gnomad OTH exome

AF:

0.00523

GnomAD4 exome

AF:

0.00384

AC:

5617

AN:

1461354

Hom.:

Cov.:

AF XY:

0.00408

AC XY:

2968

AN XY:

727042

show subpopulations

Gnomad4 AFR exome

AF:

0.000508

Gnomad4 AMR exome

AF:

0.00338

Gnomad4 ASJ exome

AF:

0.0144

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00981

Gnomad4 FIN exome

AF:

0.00189

Gnomad4 NFE exome

AF:

0.00335

Gnomad4 OTH exome

AF:

0.00530

GnomAD4 genome

AF:

0.00367

AC:

558

AN:

152190

Hom.:

Cov.:

AF XY:

0.00391

AC XY:

291

AN XY:

74406

show subpopulations

Gnomad4 AFR

AF:

0.000506

Gnomad4 AMR

AF:

0.00857

Gnomad4 ASJ

AF:

0.0135

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00995

Gnomad4 FIN

AF:

0.00293

Gnomad4 NFE

AF:

0.00387

Gnomad4 OTH

AF:

0.00710

Alfa

AF:

0.00474

Hom.:

Bravo

AF:

0.00349

TwinsUK

AF:

0.00216

AC:

ALSPAC

AF:

0.00467

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00465

AC:

ExAC

AF:

0.00464

AC:

564

Asia WGS

AF:

0.00260

AC:

AN:

3478

EpiCase

AF:

0.00671

EpiControl

AF:

0.00676

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2023	RNF170: BS1, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:1

Benign, no assertion criteria provided

clinical testing

Clinical Genetics, Academic Medical Center

- -

Autosomal dominant sensory ataxia 1

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Sep 21, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.44

CADD

Benign

DANN

Benign

0.93

DEOGEN2

Benign

0.14

.;T;T;.

Eigen

Benign

-0.091

Eigen_PC

Benign

0.10

FATHMM_MKL

Uncertain

0.81

LIST_S2

Uncertain

0.90

D;T;.;T

M_CAP

Benign

0.022

MetaRNN

Benign

0.0071

T;T;T;T

MetaSVM

Benign

-0.46

MutationAssessor

Benign

0.91

L;L;L;.

MutationTaster

Benign

0.85

D;D;D;D;D

PrimateAI

Uncertain

0.57

PROVEAN

Benign

0.17

N;N;N;N

REVEL

Uncertain

0.32

Sift

Benign

0.41

T;T;T;T

Sift4G

Benign

0.56

T;T;T;T

Polyphen

0.068

B;B;B;.

Vest4

0.11

MVP

0.17

MPC

0.33

ClinPred

0.0097

GERP RS

5.4

Varity_R

0.078

gMVP

0.36

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