chr5-131180109-TA-T

Position:

• 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 NM_181705.4(LYRM7):​c.37delA​(p.Thr13fs) 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 NM_181705.4 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]

LYRM7 (HGNC:):

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. Fraction of 0.883 CDS is truncated, and there are 1 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.37delA	p.Thr13fs	frameshift_variant	2/5	ENST00000379380.9	NP_859056.2
LYRM7	NM_001293735.2	c.37delA	p.Thr13fs	frameshift_variant	2/4		NP_001280664.1
LYRM7	NR_121658.2	n.114delA		non_coding_transcript_exon_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LYRM7	ENST00000379380.9	c.37delA	p.Thr13fs	frameshift_variant	2/5	1	NM_181705.4	ENSP00000368688.4
LYRM7	ENST00000507584.1	c.37delA	p.Thr13fs	frameshift_variant	2/4	2		ENSP00000423991.1
LYRM7	ENST00000510516.5	c.37delA	p.Thr13fs	frameshift_variant	2/3	2		ENSP00000423283.1
HINT1	ENST00000506207.2	n.109-8377delT		intron_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;