ENST00000324331.10:c.-305T>G

Variant names:

• chr6-5261075-T-G
• rs116440418
• ENST00000324331.10:c.-305T>G

Variant summary

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

The ENST00000324331.10(FARS2):​c.-305T>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00827 in 451,680 control chromosomes in the GnomAD database, including 114 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.020 (91 hom., cov: 34)
  • Exomes 𝑓: 0.0022 (23 hom.)
• Consequence: FARS2 ENST00000324331.10 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.23
• Publications: 1 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BP6: Variant 6-5261075-T-G is Benign according to our data. Variant chr6-5261075-T-G is described in ClinVar as Benign. ClinVar VariationId is 1233400.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0667 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000324331.10. 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.-305T>G		5_prime_UTR	Exon 1 of 7	NP_001305801.1	O95363
	FARS2	NM_001374878.1		c.-338T>G		5_prime_UTR	Exon 1 of 7	NP_001361807.1	O95363
	LYRM4	NM_020408.6	MANE Select	c.-342A>C		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.-305T>G		5_prime_UTR	Exon 1 of 7	ENSP00000316335.5	O95363
	FARS2	ENST00000897566.1		c.-1129T>G		5_prime_UTR	Exon 1 of 8	ENSP00000567625.1
	LYRM4	ENST00000330636.9	TSL:1 MANE Select	c.-342A>C		upstream_gene	N/A	ENSP00000418787.1	Q9HD34

Frequencies

GnomAD3 genomes AF: 0.0203 AC: 3082 AN: 152124 Hom.: 91 Cov.: 34

Gnomad AFR AF: 0.0690

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00772

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000771

Gnomad SAS AF: 0.00808

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00962

Gnomad NFE AF: 0.000368

Gnomad OTH AF: 0.0153

GnomAD4 exome AF: 0.00218 AC: 652 AN: 299440 Hom.: 23 Cov.: 6 AF XY: 0.00203 AC XY: 291 AN XY: 143242

African (AFR) AF: 0.0737 AC: 439 AN: 5956

American (AMR) AF: 0.0100 AC: 9 AN: 898

Ashkenazi Jewish (ASJ) AF: 0.000697 AC: 2 AN: 2868

East Asian (EAS) AF: 0.000755 AC: 2 AN: 2650

South Asian (SAS) AF: 0.00816 AC: 74 AN: 9074

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2072

Middle Eastern (MID) AF: 0.00450 AC: 3 AN: 666

European-Non Finnish (NFE) AF: 0.000291 AC: 77 AN: 264270

Other (OTH) AF: 0.00419 AC: 46 AN: 10986

GnomAD4 genome AF: 0.0203 AC: 3083 AN: 152240 Hom.: 91 Cov.: 34 AF XY: 0.0193 AC XY: 1438 AN XY: 74436

African (AFR) AF: 0.0688 AC: 2860 AN: 41570

American (AMR) AF: 0.00771 AC: 118 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3468

East Asian (EAS) AF: 0.000773 AC: 4 AN: 5174

South Asian (SAS) AF: 0.00809 AC: 39 AN: 4822

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10602

Middle Eastern (MID) AF: 0.0103 AC: 3 AN: 292

European-Non Finnish (NFE) AF: 0.000368 AC: 25 AN: 67988

Other (OTH) AF: 0.0152 AC: 32 AN: 2110

Alfa AF: 0.00787 Hom.: 9

Bravo AF: 0.0237

Asia WGS AF: 0.00866 AC: 30 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.5
DANN	Benign	0.34
PhyloP100		-2.2
PromoterAI		0.048	Neutral
Mutation Taster		=300/0	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: rs116440418; hg19: chr6-5261308;