chr5-140690932-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4BP6

The NM_002109.6(HARS1):​c.103G>A​(p.Val35Met) variant causes a missense change. The variant allele was found at a frequency of 0.000238 in 1,599,244 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00025 ( 0 hom. )

Consequence

HARS1
NM_002109.6 missense

Scores

3
8
8

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 3.95
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.3101797).
BP6
Variant 5-140690932-C-T is Benign according to our data. Variant chr5-140690932-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 351242.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
HARS1NM_002109.6 linkuse as main transcriptc.103G>A p.Val35Met missense_variant 2/13 ENST00000504156.7 NP_002100.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
HARS1ENST00000504156.7 linkuse as main transcriptc.103G>A p.Val35Met missense_variant 2/131 NM_002109.6 ENSP00000425634 P3P12081-1

Frequencies

GnomAD3 genomes
AF:
0.000112
AC:
17
AN:
152176
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000483
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.000188
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000191
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000119
AC:
30
AN:
251378
Hom.:
0
AF XY:
0.000155
AC XY:
21
AN XY:
135886
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000264
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000251
AC:
363
AN:
1447068
Hom.:
0
Cov.:
28
AF XY:
0.000250
AC XY:
180
AN XY:
721044
show subpopulations
Gnomad4 AFR exome
AF:
0.0000301
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000324
Gnomad4 OTH exome
AF:
0.0000835
GnomAD4 genome
AF:
0.000112
AC:
17
AN:
152176
Hom.:
0
Cov.:
32
AF XY:
0.0000807
AC XY:
6
AN XY:
74346
show subpopulations
Gnomad4 AFR
AF:
0.0000483
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.000188
Gnomad4 NFE
AF:
0.000191
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000206
Hom.:
0
Bravo
AF:
0.0000831
TwinsUK
AF:
0.000539
AC:
2
ALSPAC
AF:
0.00
AC:
0
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.000123
AC:
15
EpiCase
AF:
0.000327
EpiControl
AF:
0.000415

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxMar 03, 2023In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Usher syndrome type 3B Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 19, 2023This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 35 of the HARS protein (p.Val35Met). This variant is present in population databases (rs144588417, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with HARS-related conditions. ClinVar contains an entry for this variant (Variation ID: 351242). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
not specified Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsOct 28, 2022This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.41
BayesDel_addAF
Benign
-0.12
T
BayesDel_noAF
Benign
-0.11
CADD
Pathogenic
27
DANN
Uncertain
1.0
DEOGEN2
Benign
0.040
.;T;T;T;.;.;T;T
Eigen
Uncertain
0.66
Eigen_PC
Pathogenic
0.67
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Uncertain
0.97
D;D;.;D;D;D;D;D
M_CAP
Benign
0.038
D
MetaRNN
Benign
0.31
T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.37
T
MutationAssessor
Pathogenic
3.0
M;.;M;M;M;M;.;.
MutationTaster
Benign
1.0
D;D;D;D;D;D;D
PrimateAI
Uncertain
0.70
T
PROVEAN
Benign
-2.1
N;N;.;N;N;N;N;N
REVEL
Uncertain
0.36
Sift
Uncertain
0.0010
D;D;.;D;D;D;D;D
Sift4G
Uncertain
0.017
D;D;.;D;T;T;D;.
Polyphen
1.0, 1.0
.;D;D;D;.;.;D;.
Vest4
0.30
MVP
0.75
MPC
1.0
ClinPred
0.47
T
GERP RS
6.2
RBP_binding_hub_radar
0.97
RBP_regulation_power_radar
2.0
Varity_R
0.72
gMVP
0.61

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs144588417; hg19: chr5-140070517; API