chr5-140677924-C-T

Variant names:

• chr5-140677924-C-T
• rs147288996
• NM_002109.6:c.614G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002109.6(HARS1):​c.614G>A​(p.Gly205Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00223 in 1,607,964 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. G205G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0028 (3 hom., cov: 31)
  • Exomes 𝑓: 0.0022 (12 hom.)
• Consequence: HARS1 NM_002109.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 7.57
• Publications: 15 publications found

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 Gene-Disease associations (from GenCC):

• autosomal dominant Charcot-Marie-Tooth disease type 2W

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• Usher syndrome type 3B

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• Usher syndrome type 3

  Inheritance: AR Classification: SUPPORTIVE, NO_KNOWN Submitted by: Orphanet, ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010127872).
• BP6: Variant 5-140677924-C-T is Benign according to our data. Variant chr5-140677924-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 226652.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00276 (419/151910) while in subpopulation SAS AF = 0.00313 (15/4794). AF 95% confidence interval is 0.00193. There are 3 homozygotes in GnomAd4. There are 295 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002109.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HARS1	NM_002109.6	MANE Select	c.614G>A	p.Gly205Asp	missense	Exon 6 of 13	NP_002100.2
	HARS1	NM_001258041.3		c.554G>A	p.Gly185Asp	missense	Exon 6 of 13	NP_001244970.1	P12081-4
	HARS1	NM_001289094.2		c.527G>A	p.Gly176Asp	missense	Exon 6 of 13	NP_001276023.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HARS1	ENST00000504156.7	TSL:1 MANE Select	c.614G>A	p.Gly205Asp	missense	Exon 6 of 13	ENSP00000425634.1	P12081-1
	HARS1	ENST00000457527.6	TSL:1	c.554G>A	p.Gly185Asp	missense	Exon 6 of 13	ENSP00000387893.2	P12081-4
	HARS1	ENST00000942727.1		c.731G>A	p.Gly244Asp	missense	Exon 7 of 14	ENSP00000612786.1

Frequencies

GnomAD3 genomes AF: 0.00276 AC: 419 AN: 151792 Hom.: 3 Cov.: 31

Gnomad AFR AF: 0.000363

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000329

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00313

Gnomad FIN AF: 0.0211

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00222

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00284 AC: 715 AN: 251372 AF XY: 0.00283

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000463

Gnomad ASJ exome AF: 0.000596

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0175

Gnomad NFE exome AF: 0.00226

Gnomad OTH exome AF: 0.00228

GnomAD4 exome AF: 0.00218 AC: 3167 AN: 1456054 Hom.: 12 Cov.: 29 AF XY: 0.00216 AC XY: 1566 AN XY: 724832

African (AFR) AF: 0.000360 AC: 12 AN: 33360

American (AMR) AF: 0.000514 AC: 23 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.000268 AC: 7 AN: 26096

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.00137 AC: 118 AN: 86134

European-Finnish (FIN) AF: 0.0138 AC: 735 AN: 53418

Middle Eastern (MID) AF: 0.00990 AC: 57 AN: 5756

European-Non Finnish (NFE) AF: 0.00189 AC: 2094 AN: 1106716

Other (OTH) AF: 0.00201 AC: 121 AN: 60170

GnomAD4 genome AF: 0.00276 AC: 419 AN: 151910 Hom.: 3 Cov.: 31 AF XY: 0.00398 AC XY: 295 AN XY: 74206

African (AFR) AF: 0.000362 AC: 15 AN: 41412

American (AMR) AF: 0.000328 AC: 5 AN: 15222

Ashkenazi Jewish (ASJ) AF: 0.000577 AC: 2 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00313 AC: 15 AN: 4794

European-Finnish (FIN) AF: 0.0211 AC: 223 AN: 10566

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.00222 AC: 151 AN: 67966

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.00189 Hom.: 1

Bravo AF: 0.00126

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00186 AC: 16

ExAC AF: 0.00257 AC: 312

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00316

EpiControl AF: 0.00255

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	not specified (1)
-	-	1	Usher syndrome type 3B (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Uncertain	0.020
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.52	D
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.97	D
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-0.29	T
MutationAssessor	Benign	1.8	L
PhyloP100		7.6
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-5.7	D
REVEL	Uncertain	0.41
Sift	Uncertain	0.027	D
Sift4G	Uncertain	0.018	D
Polyphen		0.73	P
Vest4		0.71
MVP		0.89
MPC		1.2
ClinPred		0.054	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.79
gMVP		0.94
Mutation Taster		=71/29	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs147288996; hg19: chr5-140057509;