8-42870005-A-C

Variant names:

• chr8-42870005-A-C
• rs2128934252
• NM_030954.4:c.321T>G

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.321T>G​(p.Cys107Trp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RNF170 NM_030954.4 missense, splice_region
• Scores: Splicing: ADA: 0.007080
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 2.89
• Publications: 1 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, 0.89
• PP5: Variant 8-42870005-A-C is Pathogenic according to our data. Variant chr8-42870005-A-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1691706.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.321T>G	p.Cys107Trp	missense splice_region	Exon 4 of 7	NP_112216.3
	RNF170	NM_001160223.2		c.321T>G	p.Cys107Trp	missense splice_region	Exon 4 of 7	NP_001153695.1	Q96K19-1
	RNF170	NM_001160224.2		c.321T>G	p.Cys107Trp	missense splice_region	Exon 4 of 6	NP_001153696.1	Q96K19-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RNF170	ENST00000527424.6	TSL:1 MANE Select	c.321T>G	p.Cys107Trp	missense splice_region	Exon 4 of 7	ENSP00000434797.1	Q96K19-1
	RNF170	ENST00000534961.5	TSL:1	c.321T>G	p.Cys107Trp	missense splice_region	Exon 4 of 7	ENSP00000445725.1	Q96K19-1
	RNF170	ENST00000319104.7	TSL:1	c.321T>G	p.Cys107Trp	missense splice_region	Exon 4 of 6	ENSP00000326138.3	Q96K19-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	Inborn genetic diseases (1)
1	-	-	Spastic paraplegia 85, autosomal recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.79	D
Eigen	Uncertain	0.19
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.49	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Uncertain	0.033	D
MutationAssessor	Pathogenic	4.7	H
PhyloP100		2.9
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-11	D
REVEL	Pathogenic	0.85
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.64		Gain of catalytic residue at L105 (P = 0.0634)
MVP		0.98
MPC		1.3
ClinPred		1.0	D
GERP RS		1.9
Varity_R		0.99
gMVP		0.97
Mutation Taster		=13/87	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0071
dbscSNV1_RF	Benign	0.16
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: rs2128934252; hg19: chr8-42725148;