11-78566139-A-T

Variant names:

• chr11-78566139-A-T
• rs144653284
• NM_024678.6:c.506T>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_024678.6(NARS2):​c.506T>A​(p.Phe169Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000344 in 1,453,560 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F169C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: NARS2 NM_024678.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:1
• Conservation: PhyloP100: 3.30
• Publications: 4 publications found

Genes affected

NARS2 (HGNC:26274): (asparaginyl-tRNA synthetase 2, mitochondrial) This gene encodes a putative member of the class II family of aminoacyl-tRNA synthetases. These enzymes play a critical role in protein biosynthesis by charging tRNAs with their cognate amino acids. This protein is encoded by the nuclear genome but is likely to be imported to the mitochondrion where it is thought to catalyze the ligation of asparagine to tRNA molecules. Mutations in this gene have been associated with combined oxidative phosphorylation deficiency 24 (COXPD24). [provided by RefSeq, Mar 2015]

NARS2 Gene-Disease associations (from GenCC):

• combined oxidative phosphorylation defect type 24

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• mitochondrial disease

  Inheritance: AR Classification: MODERATE Submitted by: Illumina
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hearing loss, autosomal recessive 94

  Inheritance: AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
• Leigh syndrome

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21133888).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024678.6. 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
	NARS2	NM_024678.6	MANE Select	c.506T>A	p.Phe169Tyr	missense	Exon 4 of 14	NP_078954.4
	NARS2	NM_001425299.1		c.506T>A	p.Phe169Tyr	missense	Exon 4 of 15	NP_001412228.1
	NARS2	NM_001425300.1		c.506T>A	p.Phe169Tyr	missense	Exon 4 of 13	NP_001412229.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NARS2	ENST00000281038.10	TSL:1 MANE Select	c.506T>A	p.Phe169Tyr	missense	Exon 4 of 14	ENSP00000281038.5	Q96I59-1
	NARS2	ENST00000695360.1		c.506T>A	p.Phe169Tyr	missense	Exon 4 of 14	ENSP00000511835.1	A0A8Q3SHT5
	NARS2	ENST00000695344.1		c.506T>A	p.Phe169Tyr	missense	Exon 4 of 12	ENSP00000511819.1	A0A8Q3SHL5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000408 AC: 1 AN: 244944 AF XY: 0.00

Gnomad AFR exome AF: 0.0000621

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000344 AC: 5 AN: 1453560 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 722758

African (AFR) AF: 0.0000907 AC: 3 AN: 33074

American (AMR) AF: 0.00 AC: 0 AN: 43156

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25786

East Asian (EAS) AF: 0.00 AC: 0 AN: 39568

South Asian (SAS) AF: 0.00 AC: 0 AN: 84524

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53216

Middle Eastern (MID) AF: 0.000349 AC: 2 AN: 5738

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1108474

Other (OTH) AF: 0.00 AC: 0 AN: 60024

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	-	not provided (3)
-	1	-	Combined oxidative phosphorylation defect type 24 (1)
-	-	1	Combined oxidative phosphorylation defect type 24;C5193096:Hearing loss, autosomal recessive 94 (1)
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	20
DANN	Benign	0.93
DEOGEN2	Uncertain	0.47	T
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.091
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	0.77	N
PhyloP100		3.3
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.26
Sift	Benign	0.25	T
Sift4G	Benign	0.32	T
Polyphen		0.017	B
Vest4		0.27
MVP		0.37
MPC		0.051
ClinPred		0.16	T
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.20
gMVP		0.64
Mutation Taster		=73/27	polymorphism

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: rs144653284; hg19: chr11-78277185; COSMIC: COSV107256557; COSMIC: COSV107256557;