rs5030748

Variant names:

• chr16-75641711-T-C
• rs5030748
• NM_005548.3:c.75A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_005548.3(KARS1):​c.75A>G​(p.Arg25Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0929 in 1,613,536 control chromosomes in the GnomAD database, including 7,895 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.069 (488 hom., cov: 31)
  • Exomes 𝑓: 0.095 (7407 hom.)
• Consequence: KARS1 NM_005548.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.265
• Publications: 11 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: Labcorp Genetics (formerly Invitae), G2P
• 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=-0.6).
• BP6: Variant 16-75641711-T-C is Benign according to our data. Variant chr16-75641711-T-C is described in ClinVar as Benign. ClinVar VariationId is 226680.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.265 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.103 is higher than 0.05.

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.75A>G	p.Arg25Arg	synonymous	Exon 2 of 14	NP_005539.1
	KARS1	NM_001130089.2		c.159A>G	p.Arg53Arg	synonymous	Exon 3 of 15	NP_001123561.1
	KARS1	NM_001378148.1		c.-394A>G		5_prime_UTR	Exon 2 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.75A>G	p.Arg25Arg	synonymous	Exon 2 of 14	ENSP00000303043.3
	KARS1	ENST00000319410.9	TSL:1	c.159A>G	p.Arg53Arg	synonymous	Exon 3 of 15	ENSP00000325448.5
	KARS1	ENST00000566560.5	TSL:1	n.189A>G		non_coding_transcript_exon	Exon 2 of 7

Frequencies

GnomAD3 genomes AF: 0.0689 AC: 10483 AN: 152176 Hom.: 489 Cov.: 31

Gnomad AFR AF: 0.0198

Gnomad AMI AF: 0.0647

Gnomad AMR AF: 0.0632

Gnomad ASJ AF: 0.0841

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.0313

Gnomad FIN AF: 0.0810

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.105

Gnomad OTH AF: 0.0661

GnomAD2 exomes AF: 0.0717 AC: 18017 AN: 251200 AF XY: 0.0734

Gnomad AFR exome AF: 0.0189

Gnomad AMR exome AF: 0.0405

Gnomad ASJ exome AF: 0.0797

Gnomad EAS exome AF: 0.000272

Gnomad FIN exome AF: 0.0772

Gnomad NFE exome AF: 0.109

Gnomad OTH exome AF: 0.0772

GnomAD4 exome AF: 0.0954 AC: 139344 AN: 1461242 Hom.: 7407 Cov.: 33 AF XY: 0.0941 AC XY: 68373 AN XY: 726952

African (AFR) AF: 0.0170 AC: 568 AN: 33480

American (AMR) AF: 0.0430 AC: 1923 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0813 AC: 2124 AN: 26134

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39698

South Asian (SAS) AF: 0.0318 AC: 2741 AN: 86254

European-Finnish (FIN) AF: 0.0780 AC: 4142 AN: 53074

Middle Eastern (MID) AF: 0.0588 AC: 339 AN: 5768

European-Non Finnish (NFE) AF: 0.110 AC: 122490 AN: 1111722

Other (OTH) AF: 0.0830 AC: 5014 AN: 60388

GnomAD4 genome AF: 0.0688 AC: 10477 AN: 152294 Hom.: 488 Cov.: 31 AF XY: 0.0667 AC XY: 4964 AN XY: 74472

African (AFR) AF: 0.0198 AC: 822 AN: 41562

American (AMR) AF: 0.0631 AC: 965 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0841 AC: 292 AN: 3470

East Asian (EAS) AF: 0.000578 AC: 3 AN: 5188

South Asian (SAS) AF: 0.0313 AC: 151 AN: 4828

European-Finnish (FIN) AF: 0.0810 AC: 860 AN: 10616

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.105 AC: 7170 AN: 68014

Other (OTH) AF: 0.0640 AC: 135 AN: 2110

Alfa AF: 0.0890 Hom.: 762

Bravo AF: 0.0674

Asia WGS AF: 0.0170 AC: 60 AN: 3478

EpiCase AF: 0.105

EpiControl AF: 0.108

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	9.9
DANN	Benign	0.75
PhyloP100		0.27
Mutation Taster		=91/9	polymorphism (auto)

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: rs5030748; hg19: chr16-75675609;