rs143267922

Variant names:

• chr16-75628590-G-A
• rs143267922
• NM_005548.3:c.1674C>T

Your query was ambiguous. Multiple possible variants found:

• chr16-75628590-G-A
• chr16-75628590-G-C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_005548.3(KARS1):​c.1674C>T​(p.Leu558Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000915 in 1,614,046 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0024 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00076 (5 hom.)
• Consequence: KARS1 NM_005548.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.474
• Publications: 0 publications found

Genes affected

KARS1 (HGNC:6215): (lysyl-tRNA synthetase 1) Aminoacyl-tRNA synthetases are a class of enzymes that charge tRNAs with their cognate amino acids. Lysyl-tRNA synthetase is a homodimer localized to the cytoplasm which belongs to the class II family of tRNA synthetases. It has been shown to be a target of autoantibodies in the human autoimmune diseases, polymyositis or dermatomyositis. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

KARS1 Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 89

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• leukoencephalopathy, progressive, infantile-onset, with or without deafness

  Inheritance: AR Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• Charcot-Marie-Tooth disease recessive intermediate B

  Inheritance: AR, Unknown Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 16-75628590-G-A is Benign according to our data. Variant chr16-75628590-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 226681.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.474 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00239 (364/152358) while in subpopulation AFR AF = 0.00637 (265/41582). AF 95% confidence interval is 0.00574. There are 0 homozygotes in GnomAd4. There are 168 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 5 AR,Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005548.3. 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
	KARS1	NM_005548.3	MANE Select	c.1674C>T	p.Leu558Leu	synonymous	Exon 13 of 14	NP_005539.1	Q15046-1
	KARS1	NM_001130089.2		c.1758C>T	p.Leu586Leu	synonymous	Exon 14 of 15	NP_001123561.1	Q15046-2
	KARS1	NM_001378148.1		c.1206C>T	p.Leu402Leu	synonymous	Exon 13 of 14	NP_001365077.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KARS1	ENST00000302445.8	TSL:1 MANE Select	c.1674C>T	p.Leu558Leu	synonymous	Exon 13 of 14	ENSP00000303043.3	Q15046-1
	KARS1	ENST00000319410.9	TSL:1	c.1758C>T	p.Leu586Leu	synonymous	Exon 14 of 15	ENSP00000325448.5	Q15046-2
	KARS1	ENST00000898534.1		c.1788C>T	p.Leu596Leu	synonymous	Exon 14 of 15	ENSP00000568593.1

Frequencies

GnomAD3 genomes AF: 0.00240 AC: 365 AN: 152240 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00639

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00301

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.000456

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00134 AC: 337 AN: 251416 AF XY: 0.00118

Gnomad AFR exome AF: 0.00720

Gnomad AMR exome AF: 0.00228

Gnomad ASJ exome AF: 0.00427

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000748

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.000761 AC: 1113 AN: 1461688 Hom.: 5 Cov.: 32 AF XY: 0.000730 AC XY: 531 AN XY: 727148

African (AFR) AF: 0.00735 AC: 246 AN: 33474

American (AMR) AF: 0.00241 AC: 108 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00383 AC: 100 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86250

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

Middle Eastern (MID) AF: 0.00443 AC: 25 AN: 5640

European-Non Finnish (NFE) AF: 0.000448 AC: 498 AN: 1111976

Other (OTH) AF: 0.00224 AC: 135 AN: 60370

GnomAD4 genome AF: 0.00239 AC: 364 AN: 152358 Hom.: 0 Cov.: 33 AF XY: 0.00225 AC XY: 168 AN XY: 74510

African (AFR) AF: 0.00637 AC: 265 AN: 41582

American (AMR) AF: 0.00294 AC: 45 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00346 AC: 12 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.000456 AC: 31 AN: 68042

Other (OTH) AF: 0.00236 AC: 5 AN: 2116

Alfa AF: 0.00183 Hom.: 0

Bravo AF: 0.00326

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000600

EpiControl AF: 0.00119

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not provided (7)
-	-	3	not specified (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	8.0
DANN	Benign	0.63
PhyloP100		0.47
Mutation Taster		=91/9	polymorphism

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: rs143267922; hg19: chr16-75662488;