8-42856362-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PP3_Moderate

The NM_030954.4(RNF170):c.574G>A(p.Gly192Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000159 in 1,444,682 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: RNF170 NM_030954.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.47

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 Uncertain_significance. Variant got 4 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
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.857

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RNF170	NM_030954.4	c.574G>A	p.Gly192Arg	missense_variant	7/7	ENST00000527424.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RNF170	ENST00000527424.6	c.574G>A	p.Gly192Arg	missense_variant	7/7	1	NM_030954.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000862 AC: 2 AN: 232124 Hom.: 0 AF XY: 0.00000794 AC XY: 1 AN XY: 125868

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000577

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000932

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000159 AC: 23 AN: 1444682 Hom.: 0 Cov.: 31 AF XY: 0.0000167 AC XY: 12 AN XY: 718270

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000505

Gnomad4 SAS exome AF: 0.0000122

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000162

Gnomad4 OTH exome AF: 0.0000335

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jan 01, 2024

RNF170: PM2, PP3 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.33
Cadd	Pathogenic	32
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.10	T;T;.
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D;.;D
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.86	D;D;D
MetaSVM	Uncertain	0.74	D
MutationAssessor	Pathogenic	2.9	M;M;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-5.5	D;D;D
REVEL	Pathogenic	0.75
Sift	Uncertain	0.0060	D;D;D
Sift4G	Uncertain	0.0070	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.85
MutPred		0.64		Gain of MoRF binding (P = 0.0179);Gain of MoRF binding (P = 0.0179);.;
MVP		0.74
MPC		0.95
ClinPred		1.0	D
GERP RS		6.1
Varity_R		0.59
gMVP		0.95

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: rs1299707781; hg19: chr8-42711505;