rs938453967

Variant names:

• chr5-140677652-T-C
• rs938453967
• NM_002109.6:c.729+3A>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_002109.6(HARS1):​c.729+3A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000188 in 1,595,836 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: HARS1 NM_002109.6 splice_region, intron
• Scores: Splicing: ADA: 0.9961
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.784
• Publications: 0 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

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.729+3A>G		splice_region intron	N/A	NP_002100.2
	HARS1	NM_001258041.3		c.669+3A>G		splice_region intron	N/A	NP_001244970.1
	HARS1	NM_001289094.2		c.642+3A>G		splice_region intron	N/A	NP_001276023.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HARS1	ENST00000504156.7	TSL:1 MANE Select	c.729+3A>G		splice_region intron	N/A	ENSP00000425634.1
	HARS1	ENST00000457527.6	TSL:1	c.669+3A>G		splice_region intron	N/A	ENSP00000387893.2
	HARS1	ENST00000942728.1		c.732A>G	p.Val244Val	synonymous	Exon 7 of 13	ENSP00000612787.1

Frequencies

GnomAD3 genomes AF: 0.00000661 AC: 1 AN: 151310 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1444526 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 719966

African (AFR) AF: 0.00 AC: 0 AN: 33134

American (AMR) AF: 0.00 AC: 0 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26004

East Asian (EAS) AF: 0.00 AC: 0 AN: 39602

South Asian (SAS) AF: 0.00 AC: 0 AN: 85914

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5740

European-Non Finnish (NFE) AF: 0.00000182 AC: 2 AN: 1096212

Other (OTH) AF: 0.00 AC: 0 AN: 59798

GnomAD4 genome AF: 0.00000661 AC: 1 AN: 151310 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 73810

African (AFR) AF: 0.00 AC: 0 AN: 41080

American (AMR) AF: 0.00 AC: 0 AN: 15120

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00 AC: 0 AN: 4778

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10494

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67910

Other (OTH) AF: 0.00 AC: 0 AN: 2068

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Usher syndrome type 3B (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	21
DANN	Benign	0.82
PhyloP100		0.78

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.84
SpliceAI score (max)		0.46		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.46		Position offset: -9

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

Other links and lift over

dbSNP: rs938453967; hg19: chr5-140057237;