rs34732372

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr5-140675132-G-A
• chr5-140675132-G-C

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PP3 BP6_Very_Strong BS1 BS2

The NM_002109.6(HARS1):​c.1196C>T​(p.Ala399Val) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000824 in 1,585,242 control chromosomes in the GnomAD database, including 7 homozygotes. 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 Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A399G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0039 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00049 (6 hom.)
• Consequence: HARS1 NM_002109.6 missense, splice_region
• Scores: Splicing: ADA: 0.9922
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 6.44
• Publications: 8 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 -15 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• BP6: Variant 5-140675132-G-A is Benign according to our data. Variant chr5-140675132-G-A is described in ClinVar as Benign. ClinVar VariationId is 472988.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00393 (598/152198) while in subpopulation AFR AF = 0.0139 (578/41528). AF 95% confidence interval is 0.013. There are 1 homozygotes in GnomAd4. There are 286 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 6 AR,AD gene

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.1196C>T	p.Ala399Val	missense splice_region	Exon 11 of 13	NP_002100.2
	HARS1	NM_001258041.3		c.1136C>T	p.Ala379Val	missense splice_region	Exon 11 of 13	NP_001244970.1	P12081-4
	HARS1	NM_001289094.2		c.1109C>T	p.Ala370Val	missense splice_region	Exon 11 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.1196C>T	p.Ala399Val	missense splice_region	Exon 11 of 13	ENSP00000425634.1	P12081-1
	HARS1	ENST00000457527.6	TSL:1	c.1136C>T	p.Ala379Val	missense splice_region	Exon 11 of 13	ENSP00000387893.2	P12081-4
	HARS1	ENST00000942727.1		c.1313C>T	p.Ala438Val	missense splice_region	Exon 12 of 14	ENSP00000612786.1

Frequencies

GnomAD3 genomes AF: 0.00393 AC: 597 AN: 152080 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0139

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000786

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.00107 AC: 270 AN: 251168 AF XY: 0.000737

Gnomad AFR exome AF: 0.0155

Gnomad AMR exome AF: 0.000347

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000494 AC: 708 AN: 1433044 Hom.: 6 Cov.: 26 AF XY: 0.000425 AC XY: 304 AN XY: 714536

African (AFR) AF: 0.0184 AC: 605 AN: 32910

American (AMR) AF: 0.000515 AC: 23 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: 0.0000467 AC: 4 AN: 85710

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

Middle Eastern (MID) AF: 0.000175 AC: 1 AN: 5706

European-Non Finnish (NFE) AF: 0.00000645 AC: 7 AN: 1085872

Other (OTH) AF: 0.00114 AC: 68 AN: 59418

GnomAD4 genome AF: 0.00393 AC: 598 AN: 152198 Hom.: 1 Cov.: 32 AF XY: 0.00384 AC XY: 286 AN XY: 74404

African (AFR) AF: 0.0139 AC: 578 AN: 41528

American (AMR) AF: 0.000785 AC: 12 AN: 15286

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

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

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68006

Other (OTH) AF: 0.00190 AC: 4 AN: 2104

Alfa AF: 0.00148 Hom.: 3

Bravo AF: 0.00466

ESP6500AA AF: 0.0154 AC: 68

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00128 AC: 155

Asia WGS AF: 0.00115 AC: 5 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.41
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.038	T
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.66	T
MetaRNN	Benign	0.0047	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		6.4
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.10
Sift	Benign	0.11	T
Sift4G	Benign	0.20	T
Polyphen		0.014	B
Vest4		0.58
MVP		0.67
MPC		0.42
ClinPred		0.047	T
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.21
gMVP		0.46
Mutation Taster		=47/53	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.87
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;