5-140674274-G-C

Variant names:

• chr5-140674274-G-C
• rs747156884
• NM_002109.6:c.1513C>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002109.6(HARS1):​c.1513C>G​(p.Pro505Ala) 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. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HARS1 NM_002109.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.927

Genes affected

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07165533).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HARS1	NM_002109.6	c.1513C>G	p.Pro505Ala	missense_variant	Exon 13 of 13	ENST00000504156.7	NP_002100.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HARS1	ENST00000504156.7	c.1513C>G	p.Pro505Ala	missense_variant	Exon 13 of 13	1	NM_002109.6	ENSP00000425634.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	18
DANN	Benign	0.87
DEOGEN2	Benign	0.0052	.;T;T;T;T;.;.;T
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.51	D
LIST_S2	Benign	0.76	T;T;.;T;T;T;T;T
M_CAP	Benign	0.0040	T
MetaRNN	Benign	0.072	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.90	.;.;L;L;.;.;.;.
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.14	N;N;.;N;N;N;N;N
REVEL	Benign	0.033
Sift	Uncertain	0.012	D;D;.;D;D;D;D;D
Sift4G	Benign	0.064	T;D;.;T;T;T;T;D
Polyphen		0.0010, 0.0030	.;B;B;B;.;.;.;B
Vest4		0.20
MutPred		0.38		.;.;Gain of MoRF binding (P = 0.0128);Gain of MoRF binding (P = 0.0128);.;.;.;.;
MVP		0.39
MPC		0.40
ClinPred		0.081	T
GERP RS		-3.4
Varity_R		0.021
gMVP		0.34

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

Publications

LitVar

Other links and lift over

dbSNP: rs747156884; hg19: chr5-140053859;