5-140691655-C-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_012208.4(HARS2):c.7C>G(p.Leu3Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00221 in 1,549,654 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0028 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0022 (11 hom.)
• Consequence: HARS2 NM_012208.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 0.770

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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0035395622).
• BP6: Variant 5-140691655-C-G is Benign according to our data. Variant chr5-140691655-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 137536.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Likely_benign=2, Uncertain_significance=1}. Variant chr5-140691655-C-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00276 (421/152360) while in subpopulation SAS AF= 0.0031 (15/4832). AF 95% confidence interval is 0.00193. There are 3 homozygotes in gnomad4. There are 296 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HARS2	NM_012208.4	c.7C>G	p.Leu3Val	missense_variant	1/13	ENST00000230771.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HARS2	ENST00000230771.9	c.7C>G	p.Leu3Val	missense_variant	1/13	1	NM_012208.4	A1

Frequencies

GnomAD3 genomes AF: 0.00277 AC: 421 AN: 152242 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00310

Gnomad FIN AF: 0.0211

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00222

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00289 AC: 445 AN: 153748 Hom.: 4 AF XY: 0.00260 AC XY: 213 AN XY: 81816

Gnomad AFR exome AF: 0.000518

Gnomad AMR exome AF: 0.000566

Gnomad ASJ exome AF: 0.000473

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00127

Gnomad FIN exome AF: 0.0181

Gnomad NFE exome AF: 0.00186

Gnomad OTH exome AF: 0.00184

GnomAD4 exome AF: 0.00215 AC: 3006 AN: 1397294 Hom.: 11 Cov.: 30 AF XY: 0.00211 AC XY: 1455 AN XY: 689384

Gnomad4 AFR exome AF: 0.000380

Gnomad4 AMR exome AF: 0.000672

Gnomad4 ASJ exome AF: 0.000278

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00136

Gnomad4 FIN exome AF: 0.0137

Gnomad4 NFE exome AF: 0.00188

Gnomad4 OTH exome AF: 0.00197

GnomAD4 genome AF: 0.00276 AC: 421 AN: 152360 Hom.: 3 Cov.: 32 AF XY: 0.00397 AC XY: 296 AN XY: 74512

Gnomad4 AFR AF: 0.000361

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00310

Gnomad4 FIN AF: 0.0211

Gnomad4 NFE AF: 0.00222

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00179 Hom.: 0

Bravo AF: 0.00125

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000473 AC: 2

ESP6500EA AF: 0.000969 AC: 8

ExAC AF: 0.000733 AC: 70

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	HARS2: BP4, BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 22, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 09, 2024	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 21, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 06, 2016	p.Leu3Val in exon 1 of HARS2: This variant is not expected to have clinical sign ificance because the leucine (Leu) at this position is not conserved through spe cies, with >5 mammals having a valine (Val) at this position. Furthermore, it h as been in 0.1% (9/6124) of European chromosomes and 0.1% (10/7898) of South Asi an chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinsti tute.org, dbSNP rs186043734). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.40
Cadd	Benign	12
Dann	Benign	0.93
DEOGEN2	Benign	0.055	T;.;.;T;.;T;T;.;T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.28	N
M_CAP	Benign	0.0076	T
MetaRNN	Benign	0.0035	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.55	N;.;.;.;.;N;N;N;.
MutationTaster	Benign	1.0	D;N;N;N;N;N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.030	N;.;.;N;.;.;.;N;N
REVEL	Benign	0.077
Sift	Benign	0.24	T;.;.;T;.;.;.;T;D
Sift4G	Benign	0.68	T;.;.;T;.;.;.;T;.
Polyphen		0.0090	B;.;.;.;.;B;B;.;B
Vest4		0.12
MVP		0.39
MPC		0.15
ClinPred		0.040	T
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.12

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs186043734; hg19: chr5-140071240;