chr5-140679789-G-C

Variant names:

• chr5-140679789-G-C
• rs143473232
• NM_002109.6:c.395C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP3_Moderate

The NM_002109.6(HARS1):​c.395C>G​(p.Thr132Ser) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T132I) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HARS1 NM_002109.6 missense, splice_region
• Scores: Splicing: ADA: 0.9910
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.48
• Publications: 13 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: Likely_pathogenic. The variant received 8 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 14 uncertain in NM_002109.6
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-140679789-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 217506.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.873

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.395C>G	p.Thr132Ser	missense splice_region	Exon 4 of 13	NP_002100.2
	HARS1	NM_001258041.3		c.395C>G	p.Thr132Ser	missense splice_region	Exon 4 of 13	NP_001244970.1
	HARS1	NM_001289094.2		c.308C>G	p.Thr103Ser	missense splice_region	Exon 4 of 13	NP_001276023.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HARS1	ENST00000504156.7	TSL:1 MANE Select	c.395C>G	p.Thr132Ser	missense splice_region	Exon 4 of 13	ENSP00000425634.1
	HARS1	ENST00000457527.6	TSL:1	c.395C>G	p.Thr132Ser	missense splice_region	Exon 4 of 13	ENSP00000387893.2
	HARS1	ENST00000507746.7	TSL:5	c.395C>G	p.Thr132Ser	missense splice_region	Exon 4 of 13	ENSP00000425889.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000405 AC: 1 AN: 247136 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000889

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 24

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000153 Hom.: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Pathogenic	4.8	H
PhyloP100		9.5
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-3.8	D
REVEL	Pathogenic	0.78
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.88	P
Vest4		0.94
MutPred		0.89		Gain of relative solvent accessibility (P = 0.09)
MVP		0.96
MPC		1.2
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.94
gMVP		0.83
Mutation Taster		=146/154	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
SpliceAI score (max)		0.060		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: rs143473232; hg19: chr5-140059374;