5-131171037-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_181705.4(LYRM7):ā€‹c.17A>Gā€‹(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 (ā˜…).

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 7.2e-7 ( 0 hom. )

Consequence

LYRM7
NM_181705.4 missense, splice_region

Scores

4
15
Splicing: ADA: 0.9999
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.39
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
LYRM7NM_181705.4 linkuse as main transcriptc.17A>G p.Lys6Arg missense_variant, splice_region_variant 1/5 ENST00000379380.9 NP_859056.2 Q5U5X0
LYRM7NM_001293735.2 linkuse as main transcriptc.17A>G p.Lys6Arg missense_variant, splice_region_variant 1/4 NP_001280664.1 D6RBV5
LYRM7NR_121658.2 linkuse as main transcriptn.94A>G splice_region_variant, non_coding_transcript_exon_variant 1/3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
LYRM7ENST00000379380.9 linkuse as main transcriptc.17A>G p.Lys6Arg missense_variant, splice_region_variant 1/51 NM_181705.4 ENSP00000368688.4 Q5U5X0
LYRM7ENST00000507584.1 linkuse as main transcriptc.17A>G p.Lys6Arg missense_variant, splice_region_variant 1/42 ENSP00000423991.1 D6RBV5
LYRM7ENST00000510516.5 linkuse as main transcriptc.17A>G p.Lys6Arg missense_variant, splice_region_variant 1/32 ENSP00000423283.1 D6R994
HINT1ENST00000506207.2 linkuse as main transcriptn.236+569T>C intron_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
show subpopulations
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
LINK: link

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxMar 21, 2022Not 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;.;.
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; API