chr5-140691655-C-G

Variant names:

• chr5-140691655-C-G
• rs186043734
• NM_012208.4:c.7C>G

Variant summary

Our verdict is Benign. The variant received -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. 16/21 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
• Publications: 9 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]

HARS1 (HGNC:4816): (histidyl-tRNA synthetase 1) Aminoacyl-tRNA synthetases are a class of enzymes that charge tRNAs with their cognate amino acids. The protein encoded by this gene is a cytoplasmic enzyme which belongs to the class II family of aminoacyl-tRNA synthetases. The enzyme is responsible for the synthesis of histidyl-transfer RNA, which is essential for the incorporation of histidine into proteins. The gene is located in a head-to-head orientation with HARSL on chromosome five, where the homologous genes share a bidirectional promoter. The gene product is a frequent target of autoantibodies in the human autoimmune disease polymyositis/dermatomyositis. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2012]

HARS1 Gene-Disease associations (from GenCC):

• autosomal dominant Charcot-Marie-Tooth disease type 2W

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• Usher syndrome type 3B

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P
• Usher syndrome type 3

  Inheritance: AR Classification: SUPPORTIVE, NO_KNOWN Submitted by: Orphanet, ClinGen

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 137536.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012208.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HARS2	NM_012208.4	MANE Select	c.7C>G	p.Leu3Val	missense	Exon 1 of 13	NP_036340.1
	HARS2	NM_001363535.2		c.7C>G	p.Leu3Val	missense	Exon 1 of 14	NP_001350464.1
	HARS2	NM_001278731.2		c.7C>G	p.Leu3Val	missense	Exon 1 of 12	NP_001265660.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HARS2	ENST00000230771.9	TSL:1 MANE Select	c.7C>G	p.Leu3Val	missense	Exon 1 of 13	ENSP00000230771.3
	HARS2	ENST00000510104.5	TSL:1	n.7C>G		non_coding_transcript_exon	Exon 1 of 6	ENSP00000423530.1
	HARS2	ENST00000645065.1		c.7C>G	p.Leu3Val	missense	Exon 2 of 15	ENSP00000493571.1

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

GnomAD2 exomes AF: 0.00289 AC: 445 AN: 153748 AF XY: 0.00260

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 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

African (AFR) AF: 0.000380 AC: 12 AN: 31576

American (AMR) AF: 0.000672 AC: 24 AN: 35734

Ashkenazi Jewish (ASJ) AF: 0.000278 AC: 7 AN: 25174

East Asian (EAS) AF: 0.00 AC: 0 AN: 35744

South Asian (SAS) AF: 0.00136 AC: 108 AN: 79234

European-Finnish (FIN) AF: 0.0137 AC: 664 AN: 48418

Middle Eastern (MID) AF: 0.00986 AC: 56 AN: 5682

European-Non Finnish (NFE) AF: 0.00188 AC: 2021 AN: 1077792

Other (OTH) AF: 0.00197 AC: 114 AN: 57940

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

African (AFR) AF: 0.000361 AC: 15 AN: 41590

American (AMR) AF: 0.000392 AC: 6 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00310 AC: 15 AN: 4832

European-Finnish (FIN) AF: 0.0211 AC: 224 AN: 10628

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.00222 AC: 151 AN: 68026

Other (OTH) AF: 0.00189 AC: 4 AN: 2116

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

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.0076	T
MetaRNN	Benign	0.0035	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.55	N
PhyloP100		0.77
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.030	N
REVEL	Benign	0.077
Sift	Benign	0.24	T
Sift4G	Benign	0.68	T
Polyphen		0.0090	B
Vest4		0.12
MVP		0.39
MPC		0.15
ClinPred		0.040	T
GERP RS		5.7
PromoterAI		0.047	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.12
Mutation Taster		=299/1	polymorphism

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

Other links and lift over

dbSNP: rs186043734; hg19: chr5-140071240;