5-140688193-T-C

Variant names:

• chr5-140688193-T-C
• rs801186
• NM_002109.6:c.180+2662A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002109.6(HARS1):​c.180+2662A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.211 in 151,892 control chromosomes in the GnomAD database, including 3,396 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.21 (3396 hom., cov: 32)
• Consequence: HARS1 NM_002109.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.220
• Publications: 11 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: Labcorp Genetics (formerly Invitae), G2P
• Usher syndrome type 3

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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.214 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HARS1	NM_002109.6	MANE Select	c.180+2662A>G		intron	N/A	NP_002100.2
	HARS1	NM_001258041.3		c.180+2662A>G		intron	N/A	NP_001244970.1
	HARS1	NM_001289094.2		c.93+2662A>G		intron	N/A	NP_001276023.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HARS1	ENST00000504156.7	TSL:1 MANE Select	c.180+2662A>G		intron	N/A	ENSP00000425634.1
	HARS1	ENST00000457527.6	TSL:1	c.180+2662A>G		intron	N/A	ENSP00000387893.2
	HARS1	ENST00000674721.1		n.2943A>G		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes AF: 0.211 AC: 31971 AN: 151774 Hom.: 3397 Cov.: 32

Gnomad AFR AF: 0.218

Gnomad AMI AF: 0.156

Gnomad AMR AF: 0.190

Gnomad ASJ AF: 0.240

Gnomad EAS AF: 0.160

Gnomad SAS AF: 0.178

Gnomad FIN AF: 0.266

Gnomad MID AF: 0.146

Gnomad NFE AF: 0.209

Gnomad OTH AF: 0.191

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.211 AC: 31982 AN: 151892 Hom.: 3396 Cov.: 32 AF XY: 0.214 AC XY: 15858 AN XY: 74244

African (AFR) AF: 0.217 AC: 8999 AN: 41418

American (AMR) AF: 0.189 AC: 2886 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.240 AC: 833 AN: 3468

East Asian (EAS) AF: 0.160 AC: 827 AN: 5176

South Asian (SAS) AF: 0.178 AC: 858 AN: 4820

European-Finnish (FIN) AF: 0.266 AC: 2793 AN: 10510

Middle Eastern (MID) AF: 0.146 AC: 43 AN: 294

European-Non Finnish (NFE) AF: 0.209 AC: 14195 AN: 67934

Other (OTH) AF: 0.192 AC: 406 AN: 2114

Alfa AF: 0.206 Hom.: 1185

Bravo AF: 0.204

Asia WGS AF: 0.187 AC: 649 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	7.2
DANN	Benign	0.87
PhyloP100		0.22
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs801186; hg19: chr5-140067778;