rs139447495

Positions:

• chr5-140676721-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002109.6(HARS1):​c.1127A>G​(p.Lys376Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000927 in 1,614,194 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0047 (7 hom., cov: 32)
  • Exomes 𝑓: 0.00053 (3 hom.)
• Consequence: HARS1 NM_002109.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 3.18

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009670794).
• BP6: Variant 5-140676721-T-C is Benign according to our data. Variant chr5-140676721-T-C is described in ClinVar as [Benign]. Clinvar id is 472987.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-140676721-T-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00472 (719/152306) while in subpopulation AFR AF= 0.0164 (681/41564). AF 95% confidence interval is 0.0154. There are 7 homozygotes in gnomad4. There are 339 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HARS1	NM_002109.6	c.1127A>G	p.Lys376Arg	missense_variant	10/13	ENST00000504156.7	NP_002100.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HARS1	ENST00000504156.7	c.1127A>G	p.Lys376Arg	missense_variant	10/13	1	NM_002109.6	ENSP00000425634	P3

Frequencies

GnomAD3 genomes AF: 0.00473 AC: 720 AN: 152186 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.0165

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00122 AC: 308 AN: 251472 Hom.: 2 AF XY: 0.000868 AC XY: 118 AN XY: 135906

Gnomad AFR exome AF: 0.0161

Gnomad AMR exome AF: 0.000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000879

Gnomad OTH exome AF: 0.000814

GnomAD4 exome AF: 0.000532 AC: 778 AN: 1461888 Hom.: 3 Cov.: 31 AF XY: 0.000452 AC XY: 329 AN XY: 727248

Gnomad4 AFR exome AF: 0.0178

Gnomad4 AMR exome AF: 0.000917

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.0000683

Gnomad4 OTH exome AF: 0.000811

GnomAD4 genome AF: 0.00472 AC: 719 AN: 152306 Hom.: 7 Cov.: 32 AF XY: 0.00455 AC XY: 339 AN XY: 74480

Gnomad4 AFR AF: 0.0164

Gnomad4 AMR AF: 0.00170

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.000833 Hom.: 1

Bravo AF: 0.00510

ESP6500AA AF: 0.0172 AC: 76

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00143 AC: 173

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 24, 2019	This variant is associated with the following publications: (PMID: 22930593) -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 25, 2021	- -

Usher syndrome type 3B Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 24, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	.;T;T;T;T;.;.;T;T
Eigen	Benign	-0.12
Eigen_PC	Benign	0.032
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.90	D;D;.;D;D;D;D;D;D
MetaRNN	Benign	0.0097	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	.;.;L;L;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-1.7	N;N;.;N;N;N;N;N;N
REVEL	Benign	0.076
Sift	Benign	0.10	T;T;.;T;T;T;T;T;T
Sift4G	Benign	0.14	T;T;.;T;T;T;T;T;.
Polyphen		0.028, 0.0050, 0.015	.;B;B;B;.;.;.;B;.
Vest4		0.19
MVP		0.56
MPC		0.34
ClinPred		0.016	T
GERP RS		5.6
Varity_R		0.25
gMVP		0.51

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: rs139447495; hg19: chr5-140056306;