rs869025602

Variant names:

• chr5-131187113-A-AG
• rs869025602
• NM_181705.4:c.244+5dupG

Variant summary

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

The NM_181705.4(LYRM7):​c.244+5dupG variant causes a splice region, intron change. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: LYRM7 NM_181705.4 splice_region, intron
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 5.97

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 5-131187113-A-AG is Pathogenic according to our data. Variant chr5-131187113-A-AG is described in ClinVar as [Pathogenic]. Clinvar id is 223134.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LYRM7	NM_181705.4	c.244+5dupG		splice_region_variant, intron_variant	Intron 4 of 4	ENST00000379380.9	NP_859056.2
LYRM7	NM_001293735.2	c.162+4815dupG		intron_variant	Intron 3 of 3		NP_001280664.1
LYRM7	NR_121658.2	n.168+6947dupG		intron_variant	Intron 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LYRM7	ENST00000379380.9	c.244+4_244+5insG		splice_region_variant, intron_variant	Intron 4 of 4	1	NM_181705.4	ENSP00000368688.4
LYRM7	ENST00000507584.1	c.162+4814_162+4815insG		intron_variant	Intron 3 of 3	2		ENSP00000423991.1
LYRM7	ENST00000510516.5	c.91+6946_91+6947insG		intron_variant	Intron 2 of 2	2		ENSP00000423283.1
HINT1	ENST00000506207.2	n.109-15381_109-15380insC		intron_variant	Intron 1 of 3	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 20

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Mitochondrial complex III deficiency nuclear type 8 Pathogenic:1

Mar 02, 2016

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.76		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.31		Position offset: 0
DS_DL_spliceai		0.76		Position offset: -4

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

Publications

LitVar

Other links and lift over

dbSNP: rs869025602; hg19: chr5-130522806;