5-140691748-C-A

Variant names:

• chr5-140691748-C-A
• rs1478169956
• NM_012208.4:c.100C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_012208.4(HARS2):​c.100C>A​(p.Gln34Lys) 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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HARS2 NM_012208.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.17
• 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]

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: G2P, Labcorp Genetics (formerly Invitae)
• Usher syndrome type 3

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

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05889845).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HARS2	NM_012208.4	MANE Select	c.100C>A	p.Gln34Lys	missense	Exon 1 of 13	NP_036340.1	P49590-1
	HARS2	NM_001363535.2		c.100C>A	p.Gln34Lys	missense	Exon 1 of 14	NP_001350464.1	A0A2R8Y5P7
	HARS2	NM_001278731.2		c.100C>A	p.Gln34Lys	missense	Exon 1 of 12	NP_001265660.1	P49590-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HARS2	ENST00000230771.9	TSL:1 MANE Select	c.100C>A	p.Gln34Lys	missense	Exon 1 of 13	ENSP00000230771.3	P49590-1
	HARS2	ENST00000510104.5	TSL:1	n.100C>A		non_coding_transcript_exon	Exon 1 of 6	ENSP00000423530.1	D6R9M5
	HARS2	ENST00000926034.1		c.100C>A	p.Gln34Lys	missense	Exon 1 of 13	ENSP00000596093.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1396660 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 689262

African (AFR) AF: 0.00 AC: 0 AN: 31620

American (AMR) AF: 0.00 AC: 0 AN: 35890

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25196

East Asian (EAS) AF: 0.00 AC: 0 AN: 35872

South Asian (SAS) AF: 0.00 AC: 0 AN: 79288

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48508

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5698

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1076704

Other (OTH) AF: 0.00 AC: 0 AN: 57884

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	16
DANN	Benign	0.79
DEOGEN2	Benign	0.051	T
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.0057	T
MetaRNN	Benign	0.059	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.0	N
PhyloP100		1.2
PrimateAI	Benign	0.46	T
PROVEAN	Benign	0.20	N
REVEL	Benign	0.086
Sift	Benign	0.98	T
Sift4G	Benign	0.53	T
Polyphen		0.0020	B
Vest4		0.18
MutPred		0.55		Gain of ubiquitination at Q34 (P = 0.0114)
MVP		0.35
MPC		0.19
ClinPred		0.12	T
GERP RS		5.6
PromoterAI		-0.027	Neutral
Varity_R		0.19
Mutation Taster		=75/25	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: rs1478169956; hg19: chr5-140071333;