NM_020408.6:c.86+65T>C

Variant names:

• chr6-5260583-A-G
• rs4141761
• NM_020408.6:c.86+65T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_020408.6(LYRM4):​c.86+65T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.414 in 1,104,190 control chromosomes in the GnomAD database, including 117,690 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.36 (11967 hom., cov: 32)
  • Exomes 𝑓: 0.42 (105723 hom.)
• Consequence: LYRM4 NM_020408.6 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.13
• Publications: 6 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 6-5260583-A-G is Benign according to our data. Variant chr6-5260583-A-G is described in ClinVar as Benign. ClinVar VariationId is 1261629.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.493 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020408.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LYRM4	NM_020408.6	MANE Select	c.86+65T>C		intron	N/A	NP_065141.3
	LYRM4	NM_001164840.3		c.86+65T>C		intron	N/A	NP_001158312.1
	LYRM4	NM_001318783.1		c.86+65T>C		intron	N/A	NP_001305712.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LYRM4	ENST00000330636.9	TSL:1 MANE Select	c.86+65T>C		intron	N/A	ENSP00000418787.1
	LYRM4	ENST00000480566.5	TSL:1	c.86+65T>C		intron	N/A	ENSP00000419928.1
	LYRM4	ENST00000468929.5	TSL:1	c.86+65T>C		intron	N/A	ENSP00000418321.1

Frequencies

GnomAD3 genomes AF: 0.357 AC: 54279 AN: 151966 Hom.: 11962 Cov.: 32

Gnomad AFR AF: 0.0866

Gnomad AMI AF: 0.567

Gnomad AMR AF: 0.395

Gnomad ASJ AF: 0.387

Gnomad EAS AF: 0.476

Gnomad SAS AF: 0.508

Gnomad FIN AF: 0.542

Gnomad MID AF: 0.323

Gnomad NFE AF: 0.461

Gnomad OTH AF: 0.356

GnomAD4 exome AF: 0.423 AC: 402527 AN: 952112 Hom.: 105723 AF XY: 0.428 AC XY: 207357 AN XY: 484062

African (AFR) AF: 0.0606 AC: 1461 AN: 24124

American (AMR) AF: 0.410 AC: 13202 AN: 32164

Ashkenazi Jewish (ASJ) AF: 0.349 AC: 7639 AN: 21860

East Asian (EAS) AF: 0.461 AC: 14828 AN: 32180

South Asian (SAS) AF: 0.495 AC: 34885 AN: 70442

European-Finnish (FIN) AF: 0.539 AC: 16794 AN: 31162

Middle Eastern (MID) AF: 0.323 AC: 1038 AN: 3216

European-Non Finnish (NFE) AF: 0.426 AC: 295654 AN: 694240

Other (OTH) AF: 0.399 AC: 17026 AN: 42724

GnomAD4 genome AF: 0.357 AC: 54291 AN: 152078 Hom.: 11967 Cov.: 32 AF XY: 0.366 AC XY: 27235 AN XY: 74316

African (AFR) AF: 0.0865 AC: 3592 AN: 41532

American (AMR) AF: 0.396 AC: 6051 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.387 AC: 1341 AN: 3468

East Asian (EAS) AF: 0.476 AC: 2432 AN: 5114

South Asian (SAS) AF: 0.510 AC: 2456 AN: 4820

European-Finnish (FIN) AF: 0.542 AC: 5719 AN: 10556

Middle Eastern (MID) AF: 0.303 AC: 89 AN: 294

European-Non Finnish (NFE) AF: 0.461 AC: 31334 AN: 67974

Other (OTH) AF: 0.360 AC: 761 AN: 2112

Alfa AF: 0.393 Hom.: 1735

Bravo AF: 0.331

Asia WGS AF: 0.472 AC: 1634 AN: 3470

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Aug 06, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 21968932)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	5.9
DANN	Benign	0.34
PhyloP100		-1.1
PromoterAI		0.019	Neutral
Mutation Taster		=98/2	polymorphism (auto)

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: rs4141761; hg19: chr6-5260816; COSMIC: COSV51169759; COSMIC: COSV51169759;