8-42870005-A-G

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP7

The NM_030954.4(RNF170):​c.321T>C​(p.Cys107Cys) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,458,580 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: RNF170 NM_030954.4 splice_region, synonymous
• Scores: Splicing: ADA: 0.0004881
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.89
• Publications: 0 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: Likely_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (REVEL=0.131).
• BP7: Synonymous conserved (PhyloP=2.89 with no splicing effect.

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>C	p.Cys107Cys	splice_region synonymous	Exon 4 of 7	NP_112216.3
	RNF170	NM_001160223.2		c.321T>C	p.Cys107Cys	splice_region synonymous	Exon 4 of 7	NP_001153695.1	Q96K19-1
	RNF170	NM_001160224.2		c.321T>C	p.Cys107Cys	splice_region synonymous	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>C	p.Cys107Cys	splice_region synonymous	Exon 4 of 7	ENSP00000434797.1	Q96K19-1
	RNF170	ENST00000534961.5	TSL:1	c.321T>C	p.Cys107Cys	splice_region synonymous	Exon 4 of 7	ENSP00000445725.1	Q96K19-1
	RNF170	ENST00000319104.7	TSL:1	c.321T>C	p.Cys107Cys	splice_region synonymous	Exon 4 of 6	ENSP00000326138.3	Q96K19-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1458580 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 725820

African (AFR) AF: 0.00 AC: 0 AN: 33372

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.00 AC: 0 AN: 86190

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1109028

Other (OTH) AF: 0.00 AC: 0 AN: 60294

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	13
DANN	Benign	0.93
PhyloP100		2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00049
dbscSNV1_RF	Benign	0.042
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;