5-131171025-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_181705.4(LYRM7):c.5G>A(p.Gly2Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000158 in 1,388,238 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

LYRM7
NM_181705.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.46

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]

LYRM7 links:

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]

HINT1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.08592191).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
LYRM7	NM_181705.4 linkuse as main transcript	c.5G>A	p.Gly2Glu	missense_variant	1/5	ENST00000379380.9
LYRM7	NM_001293735.2 linkuse as main transcript	c.5G>A	p.Gly2Glu	missense_variant	1/4
LYRM7	NR_121658.2 linkuse as main transcript	n.82G>A		non_coding_transcript_exon_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
LYRM7	ENST00000379380.9 linkuse as main transcript	c.5G>A	p.Gly2Glu	missense_variant	1/5	1	NM_181705.4	P1
LYRM7	ENST00000507584.1 linkuse as main transcript	c.5G>A	p.Gly2Glu	missense_variant	1/4	2
LYRM7	ENST00000510516.5 linkuse as main transcript	c.5G>A	p.Gly2Glu	missense_variant	1/3	2
HINT1	ENST00000506207.2 linkuse as main transcript	n.236+581C>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000345

AC:

AN:

173760

Hom.:

AF XY:

0.0000417

AC XY:

AN XY:

95942

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000277

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000101

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000158

AC:

AN:

1388238

Hom.:

Cov.:

AF XY:

0.0000174

AC XY:

AN XY:

688788

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000208

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:

0.0000148

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000330

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.0000165

AC:

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 submitter

clinical testing

GeneDx

Aug 22, 2022

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

0.16

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.31

Cadd

Benign

Dann

Benign

0.84

DEOGEN2

Benign

0.0066

T;.;.

Eigen

Benign

-0.87

Eigen_PC

Benign

-0.71

FATHMM_MKL

Benign

0.37

LIST_S2

Benign

0.35

T;T;T

M_CAP

Benign

0.0032

MetaRNN

Benign

0.086

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.1

L;.;.

MutationTaster

Benign

0.84

N;N;N

PrimateAI

Uncertain

0.49

PROVEAN

Benign

0.11

N;N;N

REVEL

Benign

0.10

Sift

Benign

0.43

T;T;T

Sift4G

Benign

0.39

T;T;T

Polyphen

0.0

B;.;.

Vest4

0.14

MutPred

0.29

Loss of methylation at R3 (P = 0.0379);Loss of methylation at R3 (P = 0.0379);Loss of methylation at R3 (P = 0.0379);

MVP

0.12

MPC

0.048

ClinPred

0.060

GERP RS

3.9

Varity_R

0.062

gMVP

0.36

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over