5-140693619-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP5 BP4

The NM_012208.4(HARS2):c.137T>A(p.Leu46Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: HARS2 NM_012208.4 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 3.26

Genes affected

HARS2 (HGNC:4817): (histidyl-tRNA synthetase 2, mitochondrial) Aminoacyl-tRNA synthetases are a class of enzymes that charge tRNAs with their cognate amino acids. The protein encoded by this gene is an enzyme belonging to the class II family of aminoacyl-tRNA synthetases. Functioning in the synthesis of histidyl-transfer RNA, the enzyme plays an accessory role in the regulation of protein biosynthesis. The gene is located in a head-to-head orientation with HARS on chromosome five, where the homologous genes likely share a bidirectional promoter. Mutations in this gene are associated with the pathogenesis of Perrault syndrome, which involves ovarian dysgenesis and sensorineural hearing loss. Alternative splicing results in multiple transcript variants of this gene. [provided by RefSeq, Jul 2013]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-140693619-T-A is Pathogenic according to our data. Variant chr5-140693619-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 633638.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.33348727).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HARS2	NM_012208.4	c.137T>A	p.Leu46Gln	missense_variant	2/13	ENST00000230771.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HARS2	ENST00000230771.9	c.137T>A	p.Leu46Gln	missense_variant	2/13	1	NM_012208.4	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Perrault syndrome 2 Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet

May 20, 2019

Variant detected as compound heterozygous, together with c.259C>T in a female with perrault syndrome -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.013	T
BayesDel_noAF	Benign	-0.26
Cadd	Uncertain	23
Dann	Uncertain	0.98
DEOGEN2	Benign	0.10	T;.;.;.;.;T;T
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.33	T;T;T;T;T;T;T
MetaSVM	Benign	-0.65	T
MutationAssessor	Pathogenic	3.1	M;.;.;.;.;M;M
MutationTaster	Benign	1.0	D;D;D;D;N;N
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.7	N;.;.;.;.;.;.
REVEL	Benign	0.24
Sift	Benign	0.038	D;.;.;.;.;.;.
Sift4G	Benign	0.24	T;.;.;.;.;.;.
Polyphen		1.0	D;.;.;.;.;D;D
Vest4		0.52
MutPred		0.60		Gain of disorder (P = 0.0165);.;Gain of disorder (P = 0.0165);Gain of disorder (P = 0.0165);.;Gain of disorder (P = 0.0165);Gain of disorder (P = 0.0165);
MVP		0.66
MPC		0.18
ClinPred		0.88	D
GERP RS		3.6
Varity_R		0.24

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1562047621; hg19: chr5-140073204;