rs1301142742

Variant names:

• chr6-5260727-C-T
• rs1301142742
• NM_020408.6:c.7G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_020408.6(LYRM4):​c.7G>A​(p.Ala3Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000215 in 1,397,398 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A3V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: LYRM4 NM_020408.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.17
• Publications: 0 publications found

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]

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

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.25773942).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LYRM4	NM_020408.6	c.7G>A	p.Ala3Thr	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	c.7G>A	p.Ala3Thr	missense_variant	Exon 1 of 3	1	NM_020408.6	ENSP00000418787.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.00 AC: 0 AN: 156266 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 0.00000215 AC: 3 AN: 1397398 Hom.: 0 Cov.: 37 AF XY: 0.00000145 AC XY: 1 AN XY: 689702

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31780

American (AMR) AF: 0.00 AC: 0 AN: 36220

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25160

East Asian (EAS) AF: 0.00 AC: 0 AN: 36460

South Asian (SAS) AF: 0.00 AC: 0 AN: 79610

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44322

Middle Eastern (MID) AF: 0.000530 AC: 3 AN: 5658

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1080148

Other (OTH) AF: 0.00 AC: 0 AN: 58040

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Combined oxidative phosphorylation deficiency 19 Uncertain:1

Dec 09, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Uncertain	0.032	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	T;.;T;T;T
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Benign	0.12	N
LIST_S2	Uncertain	0.91	D;D;D;D;D
M_CAP	Benign	0.056	D
MetaRNN	Benign	0.26	T;T;T;T;T
MetaSVM	Benign	-0.83	T
PhyloP100		4.2
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-2.4	N;D;N;N;N
REVEL	Benign	0.067
Sift	Uncertain	0.010	D;D;T;D;D
Sift4G	Uncertain	0.042	D;D;D;D;D
Polyphen		0.34	B;.;D;.;.
Vest4		0.39
MutPred		0.18		Gain of phosphorylation at A3 (P = 0.06);Gain of phosphorylation at A3 (P = 0.06);Gain of phosphorylation at A3 (P = 0.06);Gain of phosphorylation at A3 (P = 0.06);Gain of phosphorylation at A3 (P = 0.06);
MVP		0.65
MPC		0.34
ClinPred		0.98	D
GERP RS		5.0
PromoterAI		-0.54	Under-expression
Varity_R		0.54
gMVP		0.064
Mutation Taster		=87/13	polymorphism

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

Other links and lift over

dbSNP: rs1301142742; hg19: chr6-5260960;