rs869025605

Positions:

• chr5-131180109-TA-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The ENST00000379380.9(LYRM7):​c.37del​(p.Thr13HisfsTer17) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 30)
• Consequence: LYRM7 ENST00000379380.9 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 4.96

Genes affected

LYRM7 (HGNC:28072): (LYR motif containing 7) Inner mitochondrial membrane complex III (CIII) is the main enzyme complex in the mitochondrial respiratory chain, and Rieske Fe-S protein (UQCRFS1) is the last catalytic subunit added to the complex. The protein encoded by this gene is a nuclear-encoded mitochondrial matrix protein that stabilizes UQCRFS1 and chaperones it to the CIII complex. Defects in this gene are a cause of mitochondrial complex III deficiency, nuclear type 8. Three transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Jun 2014]

HINT1 (HGNC:4912): (histidine triad nucleotide binding protein 1) This gene encodes a protein that hydrolyzes purine nucleotide phosphoramidates substrates, including AMP-morpholidate, AMP-N-alanine methyl ester, AMP-alpha-acetyl lysine methyl ester, and AMP-NH2. The encoded protein interacts with these substrates via a histidine triad motif. This gene is considered a tumor suppressor gene. In addition, mutations in this gene can cause autosomal recessive neuromyotonia and axonal neuropathy. There are several related pseudogenes on chromosome 7. Several transcript variants have been observed. [provided by RefSeq, Dec 2015]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 5 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-131180109-TA-T is Pathogenic according to our data. Variant chr5-131180109-TA-T is described in ClinVar as [Pathogenic]. Clinvar id is 223137.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LYRM7	NM_181705.4	c.37del	p.Thr13HisfsTer17	frameshift_variant	2/5	ENST00000379380.9	NP_859056.2
LYRM7	NM_001293735.2	c.37del	p.Thr13HisfsTer17	frameshift_variant	2/4		NP_001280664.1
LYRM7	NR_121658.2	n.114del		non_coding_transcript_exon_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LYRM7	ENST00000379380.9	c.37del	p.Thr13HisfsTer17	frameshift_variant	2/5	1	NM_181705.4	ENSP00000368688	P1
LYRM7	ENST00000507584.1	c.37del	p.Thr13HisfsTer17	frameshift_variant	2/4	2		ENSP00000423991
LYRM7	ENST00000510516.5	c.37del	p.Thr13HisfsTer17	frameshift_variant	2/3	2		ENSP00000423283
HINT1	ENST00000506207.2	n.109-8377del		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 30

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 16, 2018	The c.37delA variant has been published previously in a patient with leukoencephalopathy and mitochondrial complex III deficiency (Dallabona et al. 2016). The c.37delA variant is not observed in large population cohorts (Lek et al., 2016). The deletion causes a frameshift starting with codon Threonine 13, changes this amino acid to a Histidine residue and creates a premature Stop codon at position 17 of the new reading frame, denoted p.Thr13HisfsX17. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. In summary, we interpret c.37delA as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 10, 2017	- -

Mitochondrial complex III deficiency nuclear type 8 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 27, 2018

- -

Computational scores

Source: dbNSFP v4.3

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: rs869025605; hg19: chr5-130515802;