8-42865438-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.83

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 -18 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 NM_030954.4
• 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 GnomAd at 5 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RNF170	NM_030954.4	c.374G>A	p.Ser125Asn	missense_variant	5/7	ENST00000527424.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RNF170	ENST00000527424.6	c.374G>A	p.Ser125Asn	missense_variant	5/7	1	NM_030954.4	P1

Frequencies

GnomAD3 genomes AF: 0.00368 AC: 559 AN: 152072 Hom.: 5 Cov.: 32

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.: 7 AF XY: 0.00536 AC XY: 728 AN XY: 135798

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.: 43 Cov.: 29 AF XY: 0.00408 AC XY: 2968 AN XY: 727042

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.: 5 Cov.: 32 AF XY: 0.00391 AC XY: 291 AN XY: 74406

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.: 8

Bravo AF: 0.00349

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00467 AC: 18

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00465 AC: 40

ExAC AF: 0.00464 AC: 564

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.00671

EpiControl AF: 0.00676

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2023	RNF170: BS1, BS2 -

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	T
BayesDel_noAF	Benign	-0.44
Cadd	Benign	21
Dann	Benign	0.93
Eigen	Benign	-0.091
Eigen_PC	Benign	0.10
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.90	D;T;.;T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.0071	T;T;T;T
MetaSVM	Benign	-0.46	T
MutationAssessor	Benign	0.91	L;L;L;.
MutationTaster	Benign	0.85	D;D;D;D;D
PrimateAI	Uncertain	0.57	T
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	T
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

Other links and lift over

dbSNP: rs144435181; hg19: chr8-42720581;