5-131171037-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_181705.4(LYRM7):c.17A>G(p.Lys6Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000725 in 1,379,710 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K6N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: LYRM7 NM_181705.4 missense, splice_region
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.39

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LYRM7	NM_181705.4	c.17A>G	p.Lys6Arg	missense_variant, splice_region_variant	1/5	ENST00000379380.9
LYRM7	NM_001293735.2	c.17A>G	p.Lys6Arg	missense_variant, splice_region_variant	1/4
LYRM7	NR_121658.2	n.94A>G		splice_region_variant, non_coding_transcript_exon_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LYRM7	ENST00000379380.9	c.17A>G	p.Lys6Arg	missense_variant, splice_region_variant	1/5	1	NM_181705.4	P1
LYRM7	ENST00000507584.1	c.17A>G	p.Lys6Arg	missense_variant, splice_region_variant	1/4	2
LYRM7	ENST00000510516.5	c.17A>G	p.Lys6Arg	missense_variant, splice_region_variant	1/3	2
HINT1	ENST00000506207.2	n.236+569T>C		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.25e-7 AC: 1 AN: 1379710 Hom.: 0 Cov.: 30 AF XY: 0.00000146 AC XY: 1 AN XY: 684418

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: 9.25e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Mar 21, 2022

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	0.011	T
BayesDel_noAF	Benign	-0.22
Cadd	Pathogenic	27
Dann	Uncertain	0.99
DEOGEN2	Benign	0.015	T;.;.
Eigen	Benign	-0.095
Eigen_PC	Benign	0.015
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.47	T;T;T
M_CAP	Benign	0.044	D
MetaRNN	Benign	0.21	T;T;T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	1.9	L;.;.
MutationTaster	Benign	0.95	D;D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.55	N;N;N
REVEL	Benign	0.12
Sift	Uncertain	0.027	D;D;T
Sift4G	Uncertain	0.056	T;T;T
Polyphen		0.0030	B;.;.
Vest4		0.41
MutPred		0.33		Loss of methylation at K6 (P = 0.0216);Loss of methylation at K6 (P = 0.0216);Loss of methylation at K6 (P = 0.0216);
MVP		0.53
MPC		0.037
ClinPred		0.64	D
GERP RS		4.7
Varity_R		0.22
gMVP		0.16

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.88		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.34		Position offset: -29
DS_DL_spliceai		0.88		Position offset: 1

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-130506730;