5-140674735-C-T

Variant names:

• chr5-140674735-C-T
• rs199615869
• NM_002109.6:c.1402G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS1

The NM_002109.6(HARS1):​c.1402G>A​(p.Glu468Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00014 in 1,614,196 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: HARS1 NM_002109.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:1
• Conservation: PhyloP100: 6.08
• Publications: 2 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: Likely_benign. The variant received -4 ACMG points.

• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000138 (21/152322) while in subpopulation NFE AF = 0.00025 (17/68022). AF 95% confidence interval is 0.000159. There are 0 homozygotes in GnomAd4. There are 10 alleles in the male GnomAd4 subpopulation. Median coverage is 33. 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.1402G>A	p.Glu468Lys	missense	Exon 12 of 13	NP_002100.2
	HARS1	NM_001258041.3		c.1342G>A	p.Glu448Lys	missense	Exon 12 of 13	NP_001244970.1	P12081-4
	HARS1	NM_001289094.2		c.1315G>A	p.Glu439Lys	missense	Exon 12 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.1402G>A	p.Glu468Lys	missense	Exon 12 of 13	ENSP00000425634.1	P12081-1
	HARS1	ENST00000457527.6	TSL:1	c.1342G>A	p.Glu448Lys	missense	Exon 12 of 13	ENSP00000387893.2	P12081-4
	HARS1	ENST00000942727.1		c.1519G>A	p.Glu507Lys	missense	Exon 13 of 14	ENSP00000612786.1

Frequencies

GnomAD3 genomes AF: 0.000138 AC: 21 AN: 152204 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000965

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: 0.000250

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000103 AC: 26 AN: 251428 AF XY: 0.0000883

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000185

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000140 AC: 205 AN: 1461874 Hom.: 0 Cov.: 34 AF XY: 0.000135 AC XY: 98 AN XY: 727242

African (AFR) AF: 0.0000597 AC: 2 AN: 33478

American (AMR) AF: 0.0000671 AC: 3 AN: 44724

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53418

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

European-Non Finnish (NFE) AF: 0.000171 AC: 190 AN: 1112002

Other (OTH) AF: 0.000149 AC: 9 AN: 60394

GnomAD4 genome AF: 0.000138 AC: 21 AN: 152322 Hom.: 0 Cov.: 33 AF XY: 0.000134 AC XY: 10 AN XY: 74480

African (AFR) AF: 0.0000962 AC: 4 AN: 41568

American (AMR) AF: 0.00 AC: 0 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000250 AC: 17 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000268 Hom.: 0

Bravo AF: 0.000128

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ExAC AF: 0.000140 AC: 17

EpiCase AF: 0.000327

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Uncertain	0.064	T
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.076	T
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.56	D
MetaSVM	Uncertain	-0.049	T
MutationAssessor	Benign	1.9	L
PhyloP100		6.1
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-3.1	D
REVEL	Pathogenic	0.69
Sift	Benign	0.26	T
Sift4G	Benign	0.20	T
Polyphen		0.61	P
Vest4		0.86
MVP		0.90
MPC		1.2
ClinPred		0.32	T
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.80
gMVP		0.81
Mutation Taster		=34/66	disease causing

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: rs199615869; hg19: chr5-140054320; COSMIC: COSV56906418; COSMIC: COSV56906418;