NM_030954.4:c.595C>T

Variant names:

• chr8-42856341-G-A
• rs397514478
• NM_030954.4:c.595C>T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_Very_Strong

The NM_030954.4(RNF170):​c.595C>T​(p.Arg199Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000139 in 1,439,842 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 Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: RNF170 NM_030954.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 5.16
• Publications: 13 publications found

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)

ENSG00000286837 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.845
• PP5: Variant 8-42856341-G-A is Pathogenic according to our data. Variant chr8-42856341-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 31590.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RNF170	NM_030954.4	MANE Select	c.595C>T	p.Arg199Cys	missense	Exon 7 of 7	NP_112216.3
	RNF170	NM_001160223.2		c.595C>T	p.Arg199Cys	missense	Exon 7 of 7	NP_001153695.1	Q96K19-1
	RNF170	NM_001160225.2		c.343C>T	p.Arg115Cys	missense	Exon 7 of 7	NP_001153697.1	Q96K19-6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RNF170	ENST00000527424.6	TSL:1 MANE Select	c.595C>T	p.Arg199Cys	missense	Exon 7 of 7	ENSP00000434797.1	Q96K19-1
	RNF170	ENST00000534961.5	TSL:1	c.595C>T	p.Arg199Cys	missense	Exon 7 of 7	ENSP00000445725.1	Q96K19-1
	RNF170	ENST00000526349.5	TSL:1	c.343C>T	p.Arg115Cys	missense	Exon 7 of 7	ENSP00000435782.1	Q96K19-6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000439 AC: 1 AN: 227970 AF XY: 0.00000809

Gnomad AFR exome AF: 0.0000634

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000139 AC: 2 AN: 1439842 Hom.: 0 Cov.: 31 AF XY: 0.00000140 AC XY: 1 AN XY: 715804

African (AFR) AF: 0.0000314 AC: 1 AN: 31814

American (AMR) AF: 0.00 AC: 0 AN: 38036

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24990

East Asian (EAS) AF: 0.00 AC: 0 AN: 39582

South Asian (SAS) AF: 0.00 AC: 0 AN: 81120

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52896

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5634

European-Non Finnish (NFE) AF: 9.04e-7 AC: 1 AN: 1106396

Other (OTH) AF: 0.00 AC: 0 AN: 59374

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Autosomal dominant sensory ataxia 1 (2)
1	-	-	Spastic paraplegia 85, autosomal recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Uncertain	0.68	D
MutationAssessor	Pathogenic	2.9	M
PhyloP100		5.2
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-5.1	D
REVEL	Pathogenic	0.76
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.067	T
Polyphen		0.99	D
Vest4		0.88
MutPred		0.51		Loss of solvent accessibility (P = 0.001)
MVP		0.97
MPC		0.49
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.60
gMVP		0.91
Mutation Taster		=1/99	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs397514478; hg19: chr8-42711484; COSMIC: COSV53566432; COSMIC: COSV53566432;