6-5260703-A-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_020408.6(LYRM4):c.31T>G(p.Ser11Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.277 in 1,553,322 control chromosomes in the GnomAD database, including 71,365 homozygotes. 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 Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S11S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.41 ( 16762 hom., cov: 32)

Exomes 𝑓: 0.26 ( 54603 hom. )

Consequence

LYRM4
NM_020408.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 1.36

Publications

55 publications found

Variant links:

Genes affected

LYRM4 (HGNC:21365): (LYR motif containing 4) The protein encoded by this gene is found in both mitochondria and the nucleus, where it binds cysteine desulfurase and helps free inorganic sulfur for Fe/S clusters. Disruption of this gene negatively impacts mitochondrial and cytosolic iron homeostasis. [provided by RefSeq, Sep 2016]

LYRM4 links:

FARS2 (HGNC:21062): (phenylalanyl-tRNA synthetase 2, mitochondrial) This gene encodes a protein that transfers phenylalanine to its cognate tRNA. This protein localizes to the mitochondrion and plays a role in mitochondrial protein translation. Mutations in this gene can cause combined oxidative phosphorylation deficiency 14 (Alpers encephalopathy). Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

FARS2 Gene-Disease associations (from GenCC):

metabolic disease
Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
combined oxidative phosphorylation defect type 14
Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
hereditary spastic paraplegia 77
Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
Leigh syndrome
Inheritance: AR Classification: MODERATE Submitted by: ClinGen

FARS2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.1671281E-5).

BP6

Variant 6-5260703-A-C is Benign according to our data. Variant chr6-5260703-A-C is described in ClinVar as Benign. ClinVar VariationId is 380035.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.771 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LYRM4	NM_020408.6 link	c.31T>G	p.Ser11Ala	missense_variant	Exon 1 of 3	ENST00000330636.9	NP_065141.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LYRM4	ENST00000330636.9 link	c.31T>G	p.Ser11Ala	missense_variant	Exon 1 of 3	1	NM_020408.6	ENSP00000418787.1

Frequencies

GnomAD3 genomes

AF:

0.406

AC:

61612

AN:

151740

Hom.:

16717

Cov.:

show subpopulations

Gnomad AFR

AF:

0.778

Gnomad AMI

AF:

0.156

Gnomad AMR

AF:

0.377

Gnomad ASJ

AF:

0.253

Gnomad EAS

AF:

0.262

Gnomad SAS

AF:

0.175

Gnomad FIN

AF:

0.217

Gnomad MID

AF:

0.370

Gnomad NFE

AF:

0.255

Gnomad OTH

AF:

0.392

GnomAD2 exomes

AF:

0.288

AC:

47290

AN:

164260

AF XY:

0.270

show subpopulations

Gnomad AFR exome

AF:

0.782

Gnomad AMR exome

AF:

0.361

Gnomad ASJ exome

AF:

0.256

Gnomad EAS exome

AF:

0.265

Gnomad FIN exome

AF:

0.212

Gnomad NFE exome

AF:

0.253

Gnomad OTH exome

AF:

0.285

GnomAD4 exome

AF:

0.263

AC:

368480

AN:

1401474

Hom.:

54603

Cov.:

AF XY:

0.259

AC XY:

178914

AN XY:

692054

show subpopulations

African (AFR)

AF:

0.802

AC:

25658

AN:

31986

American (AMR)

AF:

0.361

AC:

13266

AN:

36734

Ashkenazi Jewish (ASJ)

AF:

0.259

AC:

6525

AN:

25200

East Asian (EAS)

AF:

0.254

AC:

9355

AN:

36844

South Asian (SAS)

AF:

0.175

AC:

14003

AN:

79896

European-Finnish (FIN)

AF:

0.214

AC:

9602

AN:

44948

Middle Eastern (MID)

AF:

0.335

AC:

1889

AN:

5632

European-Non Finnish (NFE)

AF:

0.251

AC:

271148

AN:

1082052

Other (OTH)

AF:

0.293

AC:

17034

AN:

58182

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

14524

29047

43571

58094

72618

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9426

18852

28278

37704

47130

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.406

AC:

61707

AN:

151848

Hom.:

16762

Cov.:

AF XY:

0.398

AC XY:

29525

AN XY:

74204

show subpopulations

African (AFR)

AF:

0.778

AC:

32216

AN:

41412

American (AMR)

AF:

0.377

AC:

5761

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.253

AC:

878

AN:

3468

East Asian (EAS)

AF:

0.262

AC:

1340

AN:

5120

South Asian (SAS)

AF:

0.174

AC:

833

AN:

4796

European-Finnish (FIN)

AF:

0.217

AC:

2292

AN:

10550

Middle Eastern (MID)

AF:

0.384

AC:

113

AN:

294

European-Non Finnish (NFE)

AF:

0.255

AC:

17315

AN:

67910

Other (OTH)

AF:

0.388

AC:

818

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1485

2971

4456

5942

7427

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

506

1012

1518

2024

2530

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.300

Hom.:

29165

Bravo

AF:

0.438

TwinsUK

AF:

0.258

AC:

957

ALSPAC

AF:

0.248

AC:

956

ESP6500AA

AF:

0.738

AC:

3199

ESP6500EA

AF:

0.249

AC:

2111

ExAC

AF:

0.220

AC:

23291

Asia WGS

AF:

0.257

AC:

896

AN:

3474

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Feb 20, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

not specified

Benign:1

Jan 13, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Combined oxidative phosphorylation deficiency 19

Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.58

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.092

T;.;T;T;T

Eigen

Benign

-0.60

Eigen_PC

Benign

-0.43

FATHMM_MKL

Benign

0.0047

LIST_S2

Benign

0.046

T;T;T;T;T

MetaRNN

Benign

0.000012

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

.;.;.;.;.

PhyloP100

1.4

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-1.7

N;N;N;N;N

REVEL

Benign

0.093

Sift

Benign

0.32

T;T;T;T;T

Sift4G

Benign

0.15

T;T;T;T;D

Vest4

0.061

ClinPred

0.035

GERP RS

4.2

PromoterAI

-0.028

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.34

gMVP

0.030

Mutation Taster

=96/4

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over