rs34790864
Positions:
Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_002109.6(HARS1):āc.1261C>Gā(p.Leu421Val) variant causes a missense change. The variant allele was found at a frequency of 0.000617 in 1,613,472 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (ā ā ).
Frequency
Genomes: š 0.0035 ( 3 hom., cov: 32)
Exomes š: 0.00031 ( 2 hom. )
Consequence
HARS1
NM_002109.6 missense
NM_002109.6 missense
Scores
8
8
Clinical Significance
Conservation
PhyloP100: 3.67
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]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -20 ACMG points.
BP4
?
Computational evidence support a benign effect (MetaRNN=0.0090326965).
BP6
?
Variant 5-140675067-G-C is Benign according to our data. Variant chr5-140675067-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 540208.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-140675067-G-C is described in Lovd as [Benign].
BS1
?
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00352 (536/152236) while in subpopulation AFR AF= 0.0124 (514/41536). AF 95% confidence interval is 0.0115. There are 3 homozygotes in gnomad4. There are 245 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
?
High Homozygotes in GnomAd4 at 3 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HARS1 | NM_002109.6 | c.1261C>G | p.Leu421Val | missense_variant | 11/13 | ENST00000504156.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HARS1 | ENST00000504156.7 | c.1261C>G | p.Leu421Val | missense_variant | 11/13 | 1 | NM_002109.6 | P3 |
Frequencies
GnomAD3 genomes ? AF: 0.00344 AC: 524AN: 152118Hom.: 1 Cov.: 32
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GnomAD3 exomes AF: 0.000851 AC: 214AN: 251376Hom.: 2 AF XY: 0.000596 AC XY: 81AN XY: 135856
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GnomAD4 exome AF: 0.000315 AC: 460AN: 1461236Hom.: 2 Cov.: 30 AF XY: 0.000264 AC XY: 192AN XY: 726940
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GnomAD4 genome ? AF: 0.00352 AC: 536AN: 152236Hom.: 3 Cov.: 32 AF XY: 0.00329 AC XY: 245AN XY: 74420
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ESP6500AA
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Benign:2
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Oct 23, 2020 | - - |
Benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Dec 01, 2023 | HARS1: BS1, BS2 - |
not specified Benign:1
Benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jan 03, 2019 | The p.Leu421Val variant in HARS is classified as benign because it has been iden tified in 1.2% (307/24962) of African chromosomes by gnomAD (http://gnomad.broad institute.org). ACMG/AMP criteria applied: BA1. - |
Usher syndrome type 3B Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;.;D;D;D;D;D
MetaRNN
Benign
T;T;T;T;T;T;T;T
MetaSVM
Uncertain
T
MutationTaster
Benign
D;D;D;D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;.;N;N;N;N;N
REVEL
Uncertain
Sift
Benign
T;T;.;T;T;T;T;T
Sift4G
Benign
T;T;.;T;T;T;T;T
Polyphen
0.11, 0.96, 0.20
.;B;D;D;.;.;.;B
Vest4
MVP
MPC
0.46
ClinPred
T
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Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at