rs13191012

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr6-5261059-G-A
• chr6-5261059-G-C

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.-321G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.277 in 692,584 control chromosomes in the GnomAD database, including 30,975 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.36 (11816 hom., cov: 34)
  • Exomes 𝑓: 0.25 (19159 hom.)
• Consequence: FARS2 NM_001318872.2 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 6-5261059-G-A is Benign according to our data. Variant chr6-5261059-G-A is described in ClinVar as Benign. ClinVar VariationId is 676237.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.606 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.-321G>A		5_prime_UTR	Exon 1 of 7	NP_001305801.1	O95363
	FARS2	NM_001374878.1		c.-354G>A		5_prime_UTR	Exon 1 of 7	NP_001361807.1	O95363
	LYRM4	NM_020408.6	MANE Select	c.-326C>T		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>A		5_prime_UTR	Exon 1 of 7	ENSP00000316335.5	O95363
	FARS2	ENST00000897566.1		c.-1145G>A		5_prime_UTR	Exon 1 of 8	ENSP00000567625.1
	LYRM4	ENST00000330636.9	TSL:1 MANE Select	c.-326C>T		upstream_gene	N/A	ENSP00000418787.1	Q9HD34

Frequencies

GnomAD3 genomes AF: 0.358 AC: 54382 AN: 152020 Hom.: 11783 Cov.: 34

Gnomad AFR AF: 0.612

Gnomad AMI AF: 0.155

Gnomad AMR AF: 0.357

Gnomad ASJ AF: 0.254

Gnomad EAS AF: 0.259

Gnomad SAS AF: 0.169

Gnomad FIN AF: 0.218

Gnomad MID AF: 0.360

Gnomad NFE AF: 0.254

Gnomad OTH AF: 0.355

GnomAD4 exome AF: 0.255 AC: 137612 AN: 540446 Hom.: 19159 Cov.: 8 AF XY: 0.253 AC XY: 64858 AN XY: 256446

African (AFR) AF: 0.651 AC: 6805 AN: 10454

American (AMR) AF: 0.348 AC: 588 AN: 1688

Ashkenazi Jewish (ASJ) AF: 0.257 AC: 1362 AN: 5292

East Asian (EAS) AF: 0.241 AC: 1289 AN: 5356

South Asian (SAS) AF: 0.182 AC: 2715 AN: 14886

European-Finnish (FIN) AF: 0.219 AC: 834 AN: 3816

Middle Eastern (MID) AF: 0.302 AC: 373 AN: 1236

European-Non Finnish (NFE) AF: 0.248 AC: 118294 AN: 477730

Other (OTH) AF: 0.268 AC: 5352 AN: 19988

GnomAD4 genome AF: 0.358 AC: 54472 AN: 152138 Hom.: 11816 Cov.: 34 AF XY: 0.352 AC XY: 26159 AN XY: 74372

African (AFR) AF: 0.612 AC: 25435 AN: 41528

American (AMR) AF: 0.357 AC: 5454 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.254 AC: 880 AN: 3470

East Asian (EAS) AF: 0.260 AC: 1334 AN: 5136

South Asian (SAS) AF: 0.168 AC: 811 AN: 4830

European-Finnish (FIN) AF: 0.218 AC: 2306 AN: 10602

Middle Eastern (MID) AF: 0.373 AC: 109 AN: 292

European-Non Finnish (NFE) AF: 0.254 AC: 17260 AN: 67968

Other (OTH) AF: 0.352 AC: 742 AN: 2108

Alfa AF: 0.201 Hom.: 645

Bravo AF: 0.382

Asia WGS AF: 0.245 AC: 855 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	2.6
DANN	Benign	0.96
PhyloP100		-0.62
PromoterAI		-0.0034	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: rs13191012; hg19: chr6-5261292;