chr6-5261126-A-G

Variant names:

• chr6-5261126-A-G
• rs9784870
• ENST00000324331.10:c.-254A>G

Variant summary

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

The NM_001318872.2(FARS2):​c.-254A>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 0.372 in 195,088 control chromosomes in the GnomAD database, including 17,647 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.40 (15810 hom., cov: 34)
  • Exomes 𝑓: 0.28 (1837 hom.)
• Consequence: FARS2 NM_001318872.2 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0770
• Publications: 5 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=-0.97).
• BP6: Variant 6-5261126-A-G is Benign according to our data. Variant chr6-5261126-A-G is described in ClinVar as Benign. ClinVar VariationId is 680626.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.74 is higher than 0.05.

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.-254A>G		5_prime_UTR	Exon 1 of 7	NP_001305801.1	O95363
	FARS2	NM_001374878.1		c.-287A>G		5_prime_UTR	Exon 1 of 7	NP_001361807.1	O95363
	LYRM4	NM_020408.6	MANE Select	c.-393T>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.-254A>G		5_prime_UTR	Exon 1 of 7	ENSP00000316335.5	O95363
	FARS2	ENST00000897566.1		c.-1078A>G		5_prime_UTR	Exon 1 of 8	ENSP00000567625.1
	LYRM4	ENST00000330636.9	TSL:1 MANE Select	c.-393T>C		upstream_gene	N/A	ENSP00000418787.1	Q9HD34

Frequencies

GnomAD3 genomes AF: 0.397 AC: 60395 AN: 152134 Hom.: 15768 Cov.: 34

Gnomad AFR AF: 0.747

Gnomad AMI AF: 0.155

Gnomad AMR AF: 0.373

Gnomad ASJ AF: 0.254

Gnomad EAS AF: 0.260

Gnomad SAS AF: 0.174

Gnomad FIN AF: 0.218

Gnomad MID AF: 0.373

Gnomad NFE AF: 0.255

Gnomad OTH AF: 0.387

GnomAD4 exome AF: 0.284 AC: 12165 AN: 42836 Hom.: 1837 Cov.: 4 AF XY: 0.279 AC XY: 5952 AN XY: 21360

African (AFR) AF: 0.817 AC: 683 AN: 836

American (AMR) AF: 0.348 AC: 62 AN: 178

Ashkenazi Jewish (ASJ) AF: 0.310 AC: 162 AN: 522

East Asian (EAS) AF: 0.242 AC: 100 AN: 414

South Asian (SAS) AF: 0.193 AC: 506 AN: 2618

European-Finnish (FIN) AF: 0.241 AC: 148 AN: 614

Middle Eastern (MID) AF: 0.360 AC: 49 AN: 136

European-Non Finnish (NFE) AF: 0.276 AC: 9842 AN: 35600

Other (OTH) AF: 0.320 AC: 613 AN: 1918

GnomAD4 genome AF: 0.397 AC: 60490 AN: 152252 Hom.: 15810 Cov.: 34 AF XY: 0.389 AC XY: 28978 AN XY: 74442

African (AFR) AF: 0.747 AC: 31043 AN: 41546

American (AMR) AF: 0.372 AC: 5701 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.254 AC: 880 AN: 3468

East Asian (EAS) AF: 0.260 AC: 1349 AN: 5184

South Asian (SAS) AF: 0.173 AC: 836 AN: 4832

European-Finnish (FIN) AF: 0.218 AC: 2306 AN: 10594

Middle Eastern (MID) AF: 0.388 AC: 114 AN: 294

European-Non Finnish (NFE) AF: 0.255 AC: 17310 AN: 68004

Other (OTH) AF: 0.384 AC: 810 AN: 2110

Alfa AF: 0.351 Hom.: 1610

Bravo AF: 0.428

Asia WGS AF: 0.257 AC: 896 AN: 3476

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	-0.97
CADD	Benign	5.5
DANN	Benign	0.55
PhyloP100		0.077
PromoterAI		-0.078	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: rs9784870; hg19: chr6-5261359;