5-131171038-G-C

Position:

chr5-131171038-G-C

Variant summary

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

The NM_181705.4(LYRM7):c.18G>C(p.Lys6Asn) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000261 in 1,531,720 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 (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

LYRM7
NM_181705.4 missense, splice_region

Scores

Splicing: ADA: 1.000

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.63

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:

LYRM7 (HGNC:):

LYRM7 links:

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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
LYRM7	NM_181705.4 linkuse as main transcript	c.18G>C	p.Lys6Asn	missense_variant, splice_region_variant	1/5	ENST00000379380.9	NP_859056.2	Q5U5X0
LYRM7	NM_001293735.2 linkuse as main transcript	c.18G>C	p.Lys6Asn	missense_variant, splice_region_variant	1/4		NP_001280664.1	D6RBV5
LYRM7	NR_121658.2 linkuse as main transcript	n.95G>C		splice_region_variant, non_coding_transcript_exon_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
LYRM7	ENST00000379380.9 linkuse as main transcript	c.18G>C	p.Lys6Asn	missense_variant, splice_region_variant	1/5	1	NM_181705.4	ENSP00000368688.4	Q5U5X0
LYRM7	ENST00000507584.1 linkuse as main transcript	c.18G>C	p.Lys6Asn	missense_variant, splice_region_variant	1/4	2		ENSP00000423991.1	D6RBV5
LYRM7	ENST00000510516.5 linkuse as main transcript	c.18G>C	p.Lys6Asn	missense_variant, splice_region_variant	1/3	2		ENSP00000423283.1	D6R994
HINT1	ENST00000506207.2 linkuse as main transcript	n.236+568C>G		intron_variant		5

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000145

AC:

AN:

1379548

Hom.:

Cov.:

AF XY:

0.00000146

AC XY:

AN XY:

684326

show subpopulations

Gnomad4 AFR exome

AF:

0.0000359

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

AF:

0.0000131

AC:

AN:

152172

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74348

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

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

Labcorp Genetics (formerly Invitae), Labcorp

Dec 02, 2021

This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 6 of the LYRM7 protein (p.Lys6Asn). This variant also falls at the last nucleotide of exon 1, which is part of the consensus splice site for this exon. This variant is not present in population databases (gnomAD no frequency). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with LYRM7-related conditions. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.32

BayesDel_addAF

Benign

-0.056

BayesDel_noAF

Benign

-0.32

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.11

T;.;.

Eigen

Benign

0.041

Eigen_PC

Benign

0.15

FATHMM_MKL

Benign

0.64

LIST_S2

Benign

0.68

T;T;T

M_CAP

Benign

0.036

MetaRNN

Benign

0.27

T;T;T

MetaSVM

Benign

-0.64

MutationAssessor

Benign

1.6

L;.;.

PrimateAI

Uncertain

0.69

PROVEAN

Uncertain

-2.6

D;D;D

REVEL

Benign

0.13

Sift

Benign

0.035

D;D;D

Sift4G

Uncertain

0.015

D;D;D

Polyphen

0.0030

B;.;.

Vest4

0.45

MutPred

0.33

Loss of methylation at K6 (P = 0.0059);Loss of methylation at K6 (P = 0.0059);Loss of methylation at K6 (P = 0.0059);

MVP

0.49

MPC

0.046

ClinPred

0.81

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.54

gMVP

0.34

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

1.0

SpliceAI score (max)

0.90

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.32

Position offset: 20

DS_DL_spliceai

0.90

Position offset: 0

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