rs77573084

Variant names:

• chr16-75631248-G-A
• rs77573084
• NM_005548.3:c.1258C>T

Your query was ambiguous. Multiple possible variants found:

• chr16-75631248-G-A
• chr16-75631248-G-C
• chr16-75631248-G-T

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 1P and 18B. PP3 BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_005548.3(KARS1):​c.1258C>T​(p.Arg420Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00292 in 1,613,744 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R420H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0019 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0030 (11 hom.)
• Consequence: KARS1 NM_005548.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 10.0
• Publications: 8 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 -17 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 7: BayesDel_noAF, Cadd, Eigen, phyloP100way_vertebrate, PROVEAN, REVEL, REVEL [when AlphaMissense, max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.10187775).
• BP6: Variant 16-75631248-G-A is Benign according to our data. Variant chr16-75631248-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 226679.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00193 (294/152282) while in subpopulation NFE AF = 0.00378 (257/68020). AF 95% confidence interval is 0.0034. There are 1 homozygotes in GnomAd4. There are 120 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 11 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.1258C>T	p.Arg420Cys	missense	Exon 10 of 14	NP_005539.1	Q15046-1
	KARS1	NM_001130089.2		c.1342C>T	p.Arg448Cys	missense	Exon 11 of 15	NP_001123561.1	Q15046-2
	KARS1	NM_001378148.1		c.790C>T	p.Arg264Cys	missense	Exon 10 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.1258C>T	p.Arg420Cys	missense	Exon 10 of 14	ENSP00000303043.3	Q15046-1
	KARS1	ENST00000319410.9	TSL:1	c.1342C>T	p.Arg448Cys	missense	Exon 11 of 15	ENSP00000325448.5	Q15046-2
	KARS1	ENST00000898534.1		c.1372C>T	p.Arg458Cys	missense	Exon 11 of 15	ENSP00000568593.1

Frequencies

GnomAD3 genomes AF: 0.00193 AC: 294 AN: 152164 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000700

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

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: 0.00378

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.00149 AC: 374 AN: 250636 AF XY: 0.00154

Gnomad AFR exome AF: 0.000494

Gnomad AMR exome AF: 0.000377

Gnomad ASJ exome AF: 0.0000996

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00306

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.00302 AC: 4413 AN: 1461462 Hom.: 11 Cov.: 32 AF XY: 0.00290 AC XY: 2111 AN XY: 727044

African (AFR) AF: 0.000777 AC: 26 AN: 33476

American (AMR) AF: 0.000515 AC: 23 AN: 44670

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26112

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86204

European-Finnish (FIN) AF: 0.0000562 AC: 3 AN: 53394

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

European-Non Finnish (NFE) AF: 0.00376 AC: 4175 AN: 1111772

Other (OTH) AF: 0.00306 AC: 185 AN: 60372

GnomAD4 genome AF: 0.00193 AC: 294 AN: 152282 Hom.: 1 Cov.: 33 AF XY: 0.00161 AC XY: 120 AN XY: 74456

African (AFR) AF: 0.000698 AC: 29 AN: 41564

American (AMR) AF: 0.000458 AC: 7 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

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

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

European-Non Finnish (NFE) AF: 0.00378 AC: 257 AN: 68020

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.00283 Hom.: 5

Bravo AF: 0.00208

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00337 AC: 13

ESP6500AA AF: 0.000910 AC: 4

ESP6500EA AF: 0.00302 AC: 26

ExAC AF: 0.00133 AC: 162

EpiCase AF: 0.00300

EpiControl AF: 0.00297

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	not specified (2)
-	-	1	KARS1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.060	T
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.83	D
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.10	T
MetaSVM	Uncertain	0.15	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		10
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Pathogenic	0.68
Sift	Benign	0.12	T
Sift4G	Benign	0.16	T
Polyphen		0.42	B
Vest4		0.87
MVP		0.91
MPC		0.55
ClinPred		0.075	T
GERP RS		5.9
Varity_R		0.78
gMVP		0.82
Mutation Taster		=6/94	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs77573084; hg19: chr16-75665146; COSMIC: COSV56692206; COSMIC: COSV56692206;