chr6-5261059-G-C

Variant names:

• chr6-5261059-G-C
• rs13191012
• ENST00000324331.10:c.-321G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001318872.2(FARS2):​c.-321G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000197 in 152,068 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: FARS2 NM_001318872.2 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.616
• Publications: 8 publications found

Genes affected

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]

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 Gene-Disease associations (from GenCC):

• severe neonatal lactic acidosis due to NFS1-ISD11 complex deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• combined oxidative phosphorylation deficiency 19

  Inheritance: AR, Unknown Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001318872.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FARS2	NM_001318872.2		c.-321G>C		5_prime_UTR	Exon 1 of 7	NP_001305801.1	O95363
	FARS2	NM_001374878.1		c.-354G>C		5_prime_UTR	Exon 1 of 7	NP_001361807.1	O95363
	LYRM4	NM_020408.6	MANE Select	c.-326C>G		upstream_gene	N/A	NP_065141.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FARS2	ENST00000324331.10	TSL:1	c.-321G>C		5_prime_UTR	Exon 1 of 7	ENSP00000316335.5	O95363
	FARS2	ENST00000897566.1		c.-1145G>C		5_prime_UTR	Exon 1 of 8	ENSP00000567625.1
	LYRM4	ENST00000330636.9	TSL:1 MANE Select	c.-326C>G		upstream_gene	N/A	ENSP00000418787.1	Q9HD34

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152068 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 542162 Hom.: 0 Cov.: 8 AF XY: 0.00 AC XY: 0 AN XY: 257228

African (AFR) AF: 0.00 AC: 0 AN: 10488

American (AMR) AF: 0.00 AC: 0 AN: 1694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5314

East Asian (EAS) AF: 0.00 AC: 0 AN: 5386

South Asian (SAS) AF: 0.00 AC: 0 AN: 14916

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 3828

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1242

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 479222

Other (OTH) AF: 0.00 AC: 0 AN: 20072

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152068 Hom.: 0 Cov.: 34 AF XY: 0.0000135 AC XY: 1 AN XY: 74268

African (AFR) AF: 0.00 AC: 0 AN: 41426

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 67984

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 645

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.6
DANN	Benign	0.66
PhyloP100		-0.62
PromoterAI		-0.0028	Neutral

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: rs13191012; hg19: chr6-5261292;