19-5691922-G-A

Position:

• chr19-5691922-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004793.4(LONP1):​c.*110C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0271 in 1,285,064 control chromosomes in the GnomAD database, including 611 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (56 hom., cov: 33)
  • Exomes 𝑓: 0.028 (555 hom.)
• Consequence: LONP1 NM_004793.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.795

Genes affected

LONP1 (HGNC:9479): (lon peptidase 1, mitochondrial) This gene encodes a mitochondrial matrix protein that belongs to the Lon family of ATP-dependent proteases. This protein mediates the selective degradation of misfolded, unassembled or oxidatively damaged polypeptides in the mitochondrial matrix. It may also have a chaperone function in the assembly of inner membrane protein complexes, and participate in the regulation of mitochondrial gene expression and maintenance of the integrity of the mitochondrial genome. Decreased expression of this gene has been noted in a patient with hereditary spastic paraplegia (PMID:18378094). Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Feb 2013]

RPL36 (HGNC:13631): (ribosomal protein L36) Ribosomes, the organelles that catalyze protein synthesis, consist of a small 40S subunit and a large 60S subunit. Together these subunits are composed of 4 RNA species and approximately 80 structurally distinct proteins. This gene encodes a ribosomal protein that is a component of the 60S subunit. The protein belongs to the L36E family of ribosomal proteins. It is located in the cytoplasm. Transcript variants derived from alternative splicing exist; they encode the same protein. As is typical for genes encoding ribosomal proteins, there are multiple processed pseudogenes of this gene dispersed through the genome. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 19-5691922-G-A is Benign according to our data. Variant chr19-5691922-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 1198795.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0222 (3375/152320) while in subpopulation NFE AF= 0.0359 (2440/68038). AF 95% confidence interval is 0.0347. There are 56 homozygotes in gnomad4. There are 1483 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 56 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LONP1	NM_004793.4	c.*110C>T		3_prime_UTR_variant	18/18	ENST00000360614.8
RPL36	NM_033643.3			downstream_gene_variant		ENST00000347512.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LONP1	ENST00000360614.8	c.*110C>T		3_prime_UTR_variant	18/18	1	NM_004793.4	P1
RPL36	ENST00000347512.8			downstream_gene_variant		1	NM_033643.3	P1

Frequencies

GnomAD3 genomes AF: 0.0222 AC: 3377 AN: 152202 Hom.: 56 Cov.: 33

Gnomad AFR AF: 0.00628

Gnomad AMI AF: 0.155

Gnomad AMR AF: 0.0226

Gnomad ASJ AF: 0.0173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00456

Gnomad FIN AF: 0.00330

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0359

Gnomad OTH AF: 0.0315

GnomAD4 exome AF: 0.0278 AC: 31450 AN: 1132744 Hom.: 555 Cov.: 16 AF XY: 0.0271 AC XY: 15276 AN XY: 562774

Gnomad4 AFR exome AF: 0.00463

Gnomad4 AMR exome AF: 0.0177

Gnomad4 ASJ exome AF: 0.0177

Gnomad4 EAS exome AF: 0.0000818

Gnomad4 SAS exome AF: 0.00720

Gnomad4 FIN exome AF: 0.00508

Gnomad4 NFE exome AF: 0.0329

Gnomad4 OTH exome AF: 0.0258

GnomAD4 genome AF: 0.0222 AC: 3375 AN: 152320 Hom.: 56 Cov.: 33 AF XY: 0.0199 AC XY: 1483 AN XY: 74476

Gnomad4 AFR AF: 0.00628

Gnomad4 AMR AF: 0.0225

Gnomad4 ASJ AF: 0.0173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00435

Gnomad4 FIN AF: 0.00330

Gnomad4 NFE AF: 0.0359

Gnomad4 OTH AF: 0.0312

Alfa AF: 0.0227 Hom.: 16

Bravo AF: 0.0246

Asia WGS AF: 0.00577 AC: 20 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 29, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	3.3
DANN	Benign	0.74

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: rs11551019; hg19: chr19-5691933;