rs587780441

chr8-42856296-T-Cchr8-42856296-T-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP5 BP4 BS2

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. 14/21 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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2
• Conservation: PhyloP100: 4.50

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 Likely_benign. Variant got -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 id is 130158.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=1}. Variant chr8-42856296-T-C is described in Lovd as [Likely_pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.014598697).. Strength limited to SUPPORTING due to the PP5.
• BS2: High Homozygotes in GnomAdExome at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RNF170	NM_030954.4	c.640A>G	p.Ile214Val	missense_variant	7/7	ENST00000527424.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RNF170	ENST00000527424.6	c.640A>G	p.Ile214Val	missense_variant	7/7	1	NM_030954.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152148 Hom.: 0 Cov.: 32

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

GnomAD3 exomes AF: 0.000231 AC: 52 AN: 225378 Hom.: 2 AF XY: 0.000368 AC XY: 45 AN XY: 122268

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 SAS exome AF: 0.00175

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.: 5 Cov.: 32 AF XY: 0.000184 AC XY: 131 AN XY: 712576

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000273

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00181

Gnomad4 FIN exome AF: 0.0000952

Gnomad4 NFE exome AF: 0.0000109

Gnomad4 OTH exome AF: 0.000355

GnomAD4 genome AF: 0.0000722 AC: 11 AN: 152266 Hom.: 0 Cov.: 32 AF XY: 0.000107 AC XY: 8 AN XY: 74450

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000151

ExAC AF: 0.000231 AC: 28

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 24, 2023	Variant summary: RNF170 c.640A>G (p.Ile214Val) results in a conservative amino acid change located in the domain of unknown function DUF1232 (IPR010652) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00023 in 225378 control chromosomes, including 2 homozygotes, occurring predominantly at a frequency of 0.0017 within the South Asian subpopulation in the gnomAD database, suggesting this variant may be benign. c.640A>G has been reported in the literature in the heterozygous state in an individual affected with spastic paraparesis who underwent WES, however no second variant was identified (Sahin_2022). This report does not provide unequivocal conclusions about association of the variant with autosomal recessive spastic paraplegia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted a clinical-significance assessment for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

Autosomal dominant sensory ataxia 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Mar 06, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.34
Cadd	Benign	18
Dann	Benign	0.97
DEOGEN2	Benign	0.013	T;T;.
Eigen	Benign	-0.19
Eigen_PC	Benign	0.046
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.80	T;.;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.015	T;T;T
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	0.45	N;N;.
MutationTaster	Benign	0.79	D;D;D;N;N
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.33	N;N;N
REVEL	Benign	0.22
Sift	Benign	0.31	T;T;T
Sift4G	Benign	0.52	T;T;T
Polyphen		0.0010	B;B;.
Vest4		0.052
MutPred		0.56		Loss of loop (P = 0.2237);Loss of loop (P = 0.2237);.;
MVP		0.23
MPC		0.29
ClinPred		0.83	D
GERP RS		4.8
Varity_R		0.043
gMVP		0.64

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: rs587780441; hg19: chr8-42711439;