NM_002109.6:c.679T>G

Variant names:

• chr5-140677705-A-C
• rs768076848
• NM_002109.6:c.679T>G

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS1

The NM_002109.6(HARS1):​c.679T>G​(p.Ser227Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000533 in 1,612,150 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000045 (0 hom.)
• Consequence: HARS1 NM_002109.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 7.74
• Publications: 1 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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07897431).
• BP6: Variant 5-140677705-A-C is Benign according to our data. Variant chr5-140677705-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 576600.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000133 (20/150604) while in subpopulation AMR AF = 0.00114 (17/14964). AF 95% confidence interval is 0.000723. There are 0 homozygotes in GnomAd4. There are 14 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

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.679T>G	p.Ser227Ala	missense	Exon 7 of 13	NP_002100.2
	HARS1	NM_001258041.3		c.619T>G	p.Ser207Ala	missense	Exon 7 of 13	NP_001244970.1	P12081-4
	HARS1	NM_001289094.2		c.592T>G	p.Ser198Ala	missense	Exon 7 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.679T>G	p.Ser227Ala	missense	Exon 7 of 13	ENSP00000425634.1	P12081-1
	HARS1	ENST00000457527.6	TSL:1	c.619T>G	p.Ser207Ala	missense	Exon 7 of 13	ENSP00000387893.2	P12081-4
	HARS1	ENST00000942727.1		c.796T>G	p.Ser266Ala	missense	Exon 8 of 14	ENSP00000612786.1

Frequencies

GnomAD3 genomes AF: 0.000133 AC: 20 AN: 150486 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00114

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: 0.0000443

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000131 AC: 33 AN: 251488 AF XY: 0.000103

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000452 AC: 66 AN: 1461546 Hom.: 0 Cov.: 30 AF XY: 0.0000440 AC XY: 32 AN XY: 727114

African (AFR) AF: 0.0000299 AC: 1 AN: 33472

American (AMR) AF: 0.000894 AC: 40 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000198 AC: 22 AN: 1111698

Other (OTH) AF: 0.0000497 AC: 3 AN: 60386

GnomAD4 genome AF: 0.000133 AC: 20 AN: 150604 Hom.: 0 Cov.: 31 AF XY: 0.000191 AC XY: 14 AN XY: 73448

African (AFR) AF: 0.00 AC: 0 AN: 40904

American (AMR) AF: 0.00114 AC: 17 AN: 14964

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3454

East Asian (EAS) AF: 0.00 AC: 0 AN: 5136

South Asian (SAS) AF: 0.00 AC: 0 AN: 4706

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000443 AC: 3 AN: 67768

Other (OTH) AF: 0.00 AC: 0 AN: 2070

Alfa AF: 0.000214 Hom.: 0

Bravo AF: 0.000147

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.0000494 AC: 6

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	-	1	not specified (1)
-	-	1	Usher syndrome type 3B (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.19	T
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.21
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.050	D
MetaRNN	Benign	0.079	T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	0.39	N
PhyloP100		7.7
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.26	N
REVEL	Benign	0.14
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.099	B
Vest4		0.26
MutPred		0.56		Gain of ubiquitination at K230 (P = 0.123)
MVP		0.69
MPC		0.36
ClinPred		0.19	T
GERP RS		3.2
Varity_R		0.66
gMVP		0.75
Mutation Taster		=68/32	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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: rs768076848; hg19: chr5-140057290;