chr6-5261448-A-G

Variant names:

• chr6-5261448-A-G
• rs2773320
• ENST00000324331.10:c.-22+90A>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_001318872.2(FARS2):​c.-22+90A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.358 in 152,582 control chromosomes in the GnomAD database, including 11,822 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.36 (11812 hom., cov: 33)
  • Exomes 𝑓: 0.19 (10 hom.)
• Consequence: FARS2 NM_001318872.2 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.00900
• Publications: 9 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]

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: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
• hereditary spastic paraplegia 77

  Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
• Leigh syndrome

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP6: Variant 6-5261448-A-G is Benign according to our data. Variant chr6-5261448-A-G is described in ClinVar as Benign. ClinVar VariationId is 1291334.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.609 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.-22+90A>G		intron	N/A	NP_001305801.1	O95363
	FARS2	NM_001374878.1		c.-22+57A>G		intron	N/A	NP_001361807.1	O95363
	FARS2	NM_006567.5	MANE Select	c.-234A>G		upstream_gene	N/A	NP_006558.1	O95363

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FARS2	ENST00000324331.10	TSL:1	c.-22+90A>G		intron	N/A	ENSP00000316335.5	O95363
	FARS2	ENST00000897566.1		c.-756A>G		5_prime_UTR	Exon 1 of 8	ENSP00000567625.1
	FARS2	ENST00000602691.1	TSL:3	c.-298A>G		5_prime_UTR	Exon 1 of 3	ENSP00000473394.1	R4GMX6

Frequencies

GnomAD3 genomes AF: 0.358 AC: 54369 AN: 151798 Hom.: 11779 Cov.: 33

Gnomad AFR AF: 0.615

Gnomad AMI AF: 0.155

Gnomad AMR AF: 0.357

Gnomad ASJ AF: 0.253

Gnomad EAS AF: 0.259

Gnomad SAS AF: 0.166

Gnomad FIN AF: 0.217

Gnomad MID AF: 0.363

Gnomad NFE AF: 0.254

Gnomad OTH AF: 0.355

GnomAD4 exome AF: 0.191 AC: 127 AN: 666 Hom.: 10 Cov.: 0 AF XY: 0.207 AC XY: 96 AN XY: 464

African (AFR) AF: 0.750 AC: 3 AN: 4

American (AMR) AF: 0.00 AC: 0 AN: 2

Ashkenazi Jewish (ASJ) AF: 0.500 AC: 2 AN: 4

East Asian (EAS) AF: 0.250 AC: 4 AN: 16

South Asian (SAS) AF: 0.147 AC: 15 AN: 102

European-Finnish (FIN) AF: 0.195 AC: 32 AN: 164

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.185 AC: 64 AN: 346

Other (OTH) AF: 0.250 AC: 7 AN: 28

GnomAD4 genome AF: 0.358 AC: 54459 AN: 151916 Hom.: 11812 Cov.: 33 AF XY: 0.352 AC XY: 26141 AN XY: 74252

African (AFR) AF: 0.616 AC: 25427 AN: 41302

American (AMR) AF: 0.357 AC: 5456 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.253 AC: 879 AN: 3470

East Asian (EAS) AF: 0.259 AC: 1335 AN: 5158

South Asian (SAS) AF: 0.165 AC: 795 AN: 4822

European-Finnish (FIN) AF: 0.217 AC: 2291 AN: 10556

Middle Eastern (MID) AF: 0.377 AC: 110 AN: 292

European-Non Finnish (NFE) AF: 0.254 AC: 17282 AN: 68002

Other (OTH) AF: 0.352 AC: 743 AN: 2110

Alfa AF: 0.312 Hom.: 1108

Bravo AF: 0.382

Asia WGS AF: 0.244 AC: 852 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	-0.87
CADD	Benign	7.2
DANN	Benign	0.63
PhyloP100		-0.0090
PromoterAI		-0.021	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.26		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.26		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2773320; hg19: chr6-5261681;