Variant rs746887565 details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_002109.6(HARS1):c.457G>T(p.Ala153Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,730 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

HARS1
NM_002109.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.57

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]

HARS1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HARS1	NM_002109.6 linkuse as main transcript	c.457G>T	p.Ala153Ser	missense_variant	5/13	ENST00000504156.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HARS1	ENST00000504156.7 linkuse as main transcript	c.457G>T	p.Ala153Ser	missense_variant	5/13	1	NM_002109.6	P3	P12081-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251460

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135902

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:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461730

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727166

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Usher syndrome type 3B

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 12, 2017

This variant has not been reported in the literature in individuals with HARS-related disease. 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. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with serine at codon 153 of the HARS protein (p.Ala153Ser). The alanine residue is highly conserved and there is a moderate physicochemical difference between alanine and serine. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Uncertain

-0.040

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.28

.;T;T;T;.;.

Eigen

Pathogenic

0.76

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.44

T;.;D;D;T;D

M_CAP

Benign

0.029

MetaRNN

Uncertain

0.71

D;D;D;D;D;D

MetaSVM

Uncertain

-0.28

MutationAssessor

Uncertain

2.1

M;M;M;.;.;.

MutationTaster

Benign

1.0

D;D;D;D;D;D;D;D

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-2.0

N;.;N;N;N;N

REVEL

Benign

0.27

Sift

Uncertain

0.022

D;.;D;D;D;D

Sift4G

Uncertain

0.041

D;.;D;D;D;D

Polyphen

0.93

.;P;P;.;.;.

Vest4

0.72

MutPred

0.71

Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);.;.;.;

MVP

0.79

MPC

0.99

ClinPred

0.78

GERP RS

5.7

Varity_R

0.72

gMVP

0.81

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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