chr5-131171022-T-C
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_181705.4(LYRM7):c.2T>C(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000504 in 1,388,886 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 Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000050 ( 0 hom. )
Consequence
LYRM7
NM_181705.4 start_lost
NM_181705.4 start_lost
Scores
5
4
7
Clinical Significance
Conservation
PhyloP100: 1.61
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Start lost variant, no new inframe start found.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 5-131171022-T-C is Pathogenic according to our data. Variant chr5-131171022-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1323256.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LYRM7 | NM_181705.4 | c.2T>C | p.Met1? | start_lost | 1/5 | ENST00000379380.9 | |
LYRM7 | NM_001293735.2 | c.2T>C | p.Met1? | start_lost | 1/4 | ||
LYRM7 | NR_121658.2 | n.79T>C | non_coding_transcript_exon_variant | 1/3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LYRM7 | ENST00000379380.9 | c.2T>C | p.Met1? | start_lost | 1/5 | 1 | NM_181705.4 | P1 | |
LYRM7 | ENST00000507584.1 | c.2T>C | p.Met1? | start_lost | 1/4 | 2 | |||
LYRM7 | ENST00000510516.5 | c.2T>C | p.Met1? | start_lost | 1/3 | 2 | |||
HINT1 | ENST00000506207.2 | n.236+584A>G | intron_variant, non_coding_transcript_variant | 5 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD3 exomes AF: 0.0000172 AC: 3AN: 174826Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 96614
GnomAD3 exomes
AF:
AC:
3
AN:
174826
Hom.:
AF XY:
AC XY:
0
AN XY:
96614
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.00000504 AC: 7AN: 1388886Hom.: 0 Cov.: 30 AF XY: 0.00000435 AC XY: 3AN XY: 689134
GnomAD4 exome
AF:
AC:
7
AN:
1388886
Hom.:
Cov.:
30
AF XY:
AC XY:
3
AN XY:
689134
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ExAC
?
AF:
AC:
1
Asia WGS
AF:
AC:
2
AN:
3478
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:3Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Mitochondrial complex III deficiency nuclear type 8 Pathogenic:3Uncertain:1
Pathogenic, criteria provided, single submitter | clinical testing | Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India | Jun 13, 2023 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Apr 13, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The start lost variant c.2T>Cp.Met1? in the LYRM7 gene has been reported in homozygous state in an individual affected with mitochondrial complex III deficiency Alfattal et al., 2023. This variant is reported with the allele frequency 0.001% in the gnomAD Exomes and novel not in any individuals in 1000 Genomes. The p.Met1? a variant is predicted to disrupt the initiation codon, and thus potentially may interfere with protein expression. This variant has been reported to the ClinVar database as Pathogenic. However, study on multiple affected individuals and functional studies on the pathogenicity of the variant is unavailable. This variant is predicted to cause a loss of normal protein function through protein truncation. Loss of function variants has been previously reported to be disease causing. For these reasons, this variant has been classified as Uncertain significance. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Lifecell International Pvt. Ltd | - | A Homozygote Start lost variant c.2T>C in Exon 1 of the LYRM7 gene that results in the amino acid substitution p.Met1? was identified. The observed variant has a minor allele frequency of 0.00002% in gnomAD exomes and novel genomes, respectively. The severity of the impact of this variant on the protein is medium, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic (Variant ID: 1323256).This disorder has previously been reported in mitochorial cmplex II (Molina-Berenguer M et al 2022). Based on the above evidence this variant has been classified as Likely Pathogenic according to the ACMG guidelines. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Benign
Dann
Uncertain
DEOGEN2
Benign
T;.;.
Eigen
Uncertain
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Uncertain
D;D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Benign
T
MutationTaster
Benign
D;D;D
PROVEAN
Benign
N;D;N
REVEL
Benign
Sift
Pathogenic
D;D;D
Sift4G
Pathogenic
D;D;D
Polyphen
D;.;.
Vest4
MutPred
Loss of helix (P = 0.0237);Loss of helix (P = 0.0237);Loss of helix (P = 0.0237);
MVP
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at