5-140675132-G-C

Variant names:

• chr5-140675132-G-C
• rs34732372
• NM_002109.6:c.1196C>G

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BS1_Supporting

The NM_002109.6(HARS1):​c.1196C>G​(p.Ala399Gly) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000488 in 1,433,044 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A399V) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000049 (1 hom.)
• Consequence: HARS1 NM_002109.6 missense, splice_region
• Scores: Splicing: ADA: 0.9067
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.44
• 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: Likely_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.22619602).
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.00000488 (7/1433044) while in subpopulation MID AF = 0.000701 (4/5706). AF 95% confidence interval is 0.000239. There are 1 homozygotes in GnomAdExome4. There are 5 alleles in the male GnomAdExome4 subpopulation. Median coverage is 26. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HARS1	NM_002109.6	c.1196C>G	p.Ala399Gly	missense_variant, splice_region_variant	Exon 11 of 13	ENST00000504156.7	NP_002100.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HARS1	ENST00000504156.7	c.1196C>G	p.Ala399Gly	missense_variant, splice_region_variant	Exon 11 of 13	1	NM_002109.6	ENSP00000425634.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000488 AC: 7 AN: 1433044 Hom.: 1 Cov.: 26 AF XY: 0.00000700 AC XY: 5 AN XY: 714536

African (AFR) AF: 0.00 AC: 0 AN: 32910

American (AMR) AF: 0.00 AC: 0 AN: 44682

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25976

East Asian (EAS) AF: 0.00 AC: 0 AN: 39548

South Asian (SAS) AF: 0.00 AC: 0 AN: 85710

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53222

Middle Eastern (MID) AF: 0.000701 AC: 4 AN: 5706

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1085872

Other (OTH) AF: 0.0000505 AC: 3 AN: 59418

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 20, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1196C>G (p.A399G) alteration is located in exon 11 (coding exon 11) of the HARS gene. This alteration results from a C to G substitution at nucleotide position 1196, causing the alanine (A) at amino acid position 399 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.062	T
BayesDel_noAF	Benign	-0.33
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.036	.;T;T;T;T;.;.;T
Eigen	Benign	0.11
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.83	T;T;.;T;T;T;T;T
M_CAP	Benign	0.0084	T
MetaRNN	Benign	0.23	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	.;.;M;M;.;.;.;.
PhyloP100		6.4
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-2.2	N;N;.;N;N;N;N;D
REVEL	Benign	0.066
Sift	Benign	0.23	T;T;.;T;T;T;T;T
Sift4G	Benign	0.30	T;T;.;T;T;T;T;T
Polyphen		0.0030, 0.011, 0.012	.;B;B;B;.;.;.;B
Vest4		0.48
MutPred		0.33		.;.;Loss of stability (P = 0.0714);Loss of stability (P = 0.0714);.;.;.;.;
MVP		0.64
MPC		0.41
ClinPred		0.78	D
GERP RS		5.4
Varity_R		0.32
gMVP		0.41
Mutation Taster		=48/52	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.91
dbscSNV1_RF	Benign	0.70
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: rs34732372; hg19: chr5-140054717;