rs587777433

Positions:

• chr5-131180149-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The NM_181705.4(LYRM7):​c.73G>A​(p.Asp25Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,459,190 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: LYRM7 NM_181705.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 3.71

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.767
• PP5: Variant 5-131180149-G-A is Pathogenic according to our data. Variant chr5-131180149-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 135664.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr5-131180149-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LYRM7	NM_181705.4	c.73G>A	p.Asp25Asn	missense_variant	2/5	ENST00000379380.9	NP_859056.2
LYRM7	NM_001293735.2	c.73G>A	p.Asp25Asn	missense_variant	2/4		NP_001280664.1
LYRM7	NR_121658.2	n.150G>A		non_coding_transcript_exon_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LYRM7	ENST00000379380.9	c.73G>A	p.Asp25Asn	missense_variant	2/5	1	NM_181705.4	ENSP00000368688.4
LYRM7	ENST00000507584.1	c.73G>A	p.Asp25Asn	missense_variant	2/4	2		ENSP00000423991.1
LYRM7	ENST00000510516.5	c.73G>A	p.Asp25Asn	missense_variant	2/3	2		ENSP00000423283.1
HINT1	ENST00000506207.2	n.109-8416C>T		intron_variant		5

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459190 Hom.: 0 Cov.: 28 AF XY: 0.00000138 AC XY: 1 AN XY: 726096

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 30

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Mitochondrial complex III deficiency nuclear type 8 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 01, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Uncertain	0.029	T
BayesDel_noAF	Benign	-0.20
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.49	T;.;.
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Pathogenic	0.31	D
MetaRNN	Pathogenic	0.77	D;D;D
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Pathogenic	3.2	M;.;.
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-5.0	D;D;D
REVEL	Pathogenic	0.77
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.025	D;T;D
Polyphen		1.0	D;.;.
Vest4		0.74
MutPred		0.44		Gain of MoRF binding (P = 0.0489);Gain of MoRF binding (P = 0.0489);Gain of MoRF binding (P = 0.0489);
MVP		0.62
MPC		0.29
ClinPred		1.0	D
GERP RS		4.3
Varity_R		0.81
gMVP		0.83

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: rs587777433; hg19: chr5-130515842;