chr5-140696954-C-A

Variant names:

• chr5-140696954-C-A
• rs1439213535
• NM_012208.4:c.838C>A

Variant summary

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

The NM_012208.4(HARS2):​c.838C>A​(p.Leu280Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,458 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L280V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: HARS2 NM_012208.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.591
• Publications: 0 publications found

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]

HARS2 Gene-Disease associations (from GenCC):

• Perrault syndrome 2

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), PanelApp Australia
• Perrault syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

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=0.21362963).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HARS2	NM_012208.4	c.838C>A	p.Leu280Ile	missense_variant	Exon 9 of 13	ENST00000230771.9	NP_036340.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HARS2	ENST00000230771.9	c.838C>A	p.Leu280Ile	missense_variant	Exon 9 of 13	1	NM_012208.4	ENSP00000230771.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461458 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 727040

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86168

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53370

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5648

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111878

Other (OTH) AF: 0.00 AC: 0 AN: 60364

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.080	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.36	T;.;.;.;.;.;.;.;T;T;.;T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.44
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.94	.;.;D;.;D;D;D;D;.;D;D;D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.21	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.77	T
MutationAssessor	Uncertain	2.5	M;.;.;.;.;.;.;.;M;M;.;.
PhyloP100		0.59
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-2.0	N;.;.;.;.;.;.;.;.;.;N;N
REVEL	Benign	0.17
Sift	Benign	0.065	T;.;.;.;.;.;.;.;.;.;T;T
Sift4G	Benign	0.071	T;.;.;.;.;.;.;.;.;.;T;T
Polyphen		0.94	P;.;.;.;.;.;.;.;P;P;.;D
Vest4		0.36
MutPred		0.27		Gain of helix (P = 0.0854);.;.;.;.;.;.;.;Gain of helix (P = 0.0854);Gain of helix (P = 0.0854);.;.;
MVP		0.28
MPC		0.27
ClinPred		0.52	D
GERP RS		2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.30
Mutation Taster		=71/29	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs1439213535; hg19: chr5-140076539;