ENST00000445165.2:n.114A>C

Variant names:

• chr3-183885037-A-C
• rs3792589
• ENST00000445165.2:n.114A>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000445165.2(ENSG00000293259):​n.114A>C variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000601 in 831,594 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000060 (0 hom.)
• Consequence: ENSG00000293259 ENST00000445165.2 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.75
• Publications: 5 publications found

Genes affected

ENSG00000293259 (HGNC:):

PARL (HGNC:18253): (presenilin associated rhomboid like) This gene encodes a member of the rhomboid family of intramembrane serine proteases that is localized to the inner mitochondrial membrane. The encoded protein regulates mitochondrial remodeling and apoptosis through regulated substrate proteolysis. Proteolytic processing of the encoded protein results in the release of a small peptide, P-beta, which may transit to the nucleus. Mutations in this gene may be associated with Parkinson's disease. [provided by RefSeq, May 2016]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.01).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000445165.2. 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
	PARL	NM_018622.7	MANE Select	c.-191T>G		upstream_gene	N/A	NP_061092.3
	PARL	NM_001324436.2		c.-191T>G		upstream_gene	N/A	NP_001311365.1
	PARL	NM_001037639.3		c.-191T>G		upstream_gene	N/A	NP_001032728.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENSG00000293259	ENST00000445165.2	TSL:2	n.114A>C		non_coding_transcript_exon	Exon 1 of 2
	ENSG00000293259	ENST00000833400.1		n.1A>C		non_coding_transcript_exon	Exon 1 of 2
	PARL	ENST00000317096.9	TSL:1 MANE Select	c.-191T>G		upstream_gene	N/A	ENSP00000325421.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000601 AC: 5 AN: 831594 Hom.: 0 Cov.: 11 AF XY: 0.00000238 AC XY: 1 AN XY: 420358

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 21000

American (AMR) AF: 0.00 AC: 0 AN: 29042

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18148

East Asian (EAS) AF: 0.00 AC: 0 AN: 32646

South Asian (SAS) AF: 0.00 AC: 0 AN: 59748

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30988

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2802

European-Non Finnish (NFE) AF: 0.00000836 AC: 5 AN: 598366

Other (OTH) AF: 0.00 AC: 0 AN: 38854

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 151

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.32
DANN	Benign	0.54
PhyloP100		-4.8
PromoterAI		0.13	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs3792589; hg19: chr3-183602825;