rs141539149

Variant names:

• chr16-75635969-T-C
• rs141539149
• NM_005548.3:c.612A>G

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.612A>G​(p.Thr204Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000904 in 1,614,200 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 0.00090 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00090 (4 hom.)
• Consequence: KARS1 NM_005548.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.525
• Publications: 3 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=-0.64).
• BP6: Variant 16-75635969-T-C is Benign according to our data. Variant chr16-75635969-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 227454.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.525 with no splicing effect.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.000904 (1322/1461866) while in subpopulation MID AF = 0.0213 (123/5766). AF 95% confidence interval is 0.0183. There are 4 homozygotes in GnomAdExome4. There are 685 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 4 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.612A>G	p.Thr204Thr	synonymous	Exon 5 of 14	NP_005539.1	Q15046-1
	KARS1	NM_001130089.2		c.696A>G	p.Thr232Thr	synonymous	Exon 6 of 15	NP_001123561.1	Q15046-2
	KARS1	NM_001378148.1		c.144A>G	p.Thr48Thr	synonymous	Exon 5 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.612A>G	p.Thr204Thr	synonymous	Exon 5 of 14	ENSP00000303043.3	Q15046-1
	KARS1	ENST00000319410.9	TSL:1	c.696A>G	p.Thr232Thr	synonymous	Exon 6 of 15	ENSP00000325448.5	Q15046-2
	KARS1	ENST00000566560.5	TSL:1	n.726A>G		non_coding_transcript_exon	Exon 5 of 7

Frequencies

GnomAD3 genomes AF: 0.000900 AC: 137 AN: 152216 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000289

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.0118

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000749

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00132 AC: 332 AN: 251394 AF XY: 0.00138

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00148

Gnomad ASJ exome AF: 0.0132

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00106

Gnomad OTH exome AF: 0.00245

GnomAD4 exome AF: 0.000904 AC: 1322 AN: 1461866 Hom.: 4 Cov.: 31 AF XY: 0.000942 AC XY: 685 AN XY: 727236

African (AFR) AF: 0.000687 AC: 23 AN: 33480

American (AMR) AF: 0.00157 AC: 70 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0126 AC: 328 AN: 26134

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

South Asian (SAS) AF: 0.000278 AC: 24 AN: 86254

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53420

Middle Eastern (MID) AF: 0.0213 AC: 123 AN: 5766

European-Non Finnish (NFE) AF: 0.000543 AC: 604 AN: 1111992

Other (OTH) AF: 0.00247 AC: 149 AN: 60396

GnomAD4 genome AF: 0.000899 AC: 137 AN: 152334 Hom.: 1 Cov.: 32 AF XY: 0.000859 AC XY: 64 AN XY: 74492

African (AFR) AF: 0.000289 AC: 12 AN: 41580

American (AMR) AF: 0.00111 AC: 17 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0118 AC: 41 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.000750 AC: 51 AN: 68040

Other (OTH) AF: 0.00473 AC: 10 AN: 2114

Alfa AF: 0.00158 Hom.: 0

Bravo AF: 0.00108

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00180

EpiControl AF: 0.00166

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)
-	-	1	KARS1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	3.1
DANN	Benign	0.66
PhyloP100		-0.53
PromoterAI		0.033	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=97/3	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: rs141539149; hg19: chr16-75669867;