8-42856296-T-G

Variant names:

• chr8-42856296-T-G
• rs587780441
• NM_030954.4:c.640A>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM2 PM5 BP4_Moderate

The NM_030954.4(RNF170):​c.640A>C​(p.Ile214Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000697 in 1,434,410 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I214V) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: RNF170 NM_030954.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.50
• Publications: 2 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr8-42856296-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 130158.
• BP4: Computational evidence support a benign effect (MetaRNN=0.13078982).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RNF170	NM_030954.4	MANE Select	c.640A>C	p.Ile214Leu	missense	Exon 7 of 7	NP_112216.3
	RNF170	NM_001160223.2		c.640A>C	p.Ile214Leu	missense	Exon 7 of 7	NP_001153695.1
	RNF170	NM_001160225.2		c.388A>C	p.Ile130Leu	missense	Exon 7 of 7	NP_001153697.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RNF170	ENST00000527424.6	TSL:1 MANE Select	c.640A>C	p.Ile214Leu	missense	Exon 7 of 7	ENSP00000434797.1
	RNF170	ENST00000534961.5	TSL:1	c.640A>C	p.Ile214Leu	missense	Exon 7 of 7	ENSP00000445725.1
	RNF170	ENST00000526349.5	TSL:1	c.388A>C	p.Ile130Leu	missense	Exon 7 of 7	ENSP00000435782.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.97e-7 AC: 1 AN: 1434410 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 712576

African (AFR) AF: 0.00 AC: 0 AN: 31562

American (AMR) AF: 0.00 AC: 0 AN: 36664

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24688

East Asian (EAS) AF: 0.00 AC: 0 AN: 39556

South Asian (SAS) AF: 0.00 AC: 0 AN: 80692

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52510

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5588

European-Non Finnish (NFE) AF: 9.06e-7 AC: 1 AN: 1104054

Other (OTH) AF: 0.00 AC: 0 AN: 59096

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.024	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	20
DANN	Benign	0.90
DEOGEN2	Benign	0.015	T
Eigen	Benign	-0.18
Eigen_PC	Benign	0.058
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.62	T
MutationAssessor	Benign	0.34	N
PhyloP100		4.5
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-0.31	N
REVEL	Benign	0.17
Sift	Benign	0.46	T
Sift4G	Benign	0.97	T
Polyphen		0.0010	B
Vest4		0.24
MutPred		0.58		Gain of loop (P = 0.2045)
MVP		0.39
MPC		0.35
ClinPred		0.69	D
GERP RS		4.8
Varity_R		0.089
gMVP		0.77
Mutation Taster		=76/24	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs587780441; hg19: chr8-42711439;