chr16-75634190-G-C

Variant names:

• chr16-75634190-G-C
• rs1555513082
• NM_005548.3:c.898C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The ENST00000302445.8(KARS1):​c.898C>G​(p.Pro300Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P300S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KARS1 ENST00000302445.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 10.0
• 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: 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.963

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000302445.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KARS1	NM_005548.3	MANE Select	c.898C>G	p.Pro300Ala	missense	Exon 7 of 14	NP_005539.1
	KARS1	NM_001130089.2		c.982C>G	p.Pro328Ala	missense	Exon 8 of 15	NP_001123561.1
	KARS1	NM_001378148.1		c.430C>G	p.Pro144Ala	missense	Exon 7 of 14	NP_001365077.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KARS1	ENST00000302445.8	TSL:1 MANE Select	c.898C>G	p.Pro300Ala	missense	Exon 7 of 14	ENSP00000303043.3
	KARS1	ENST00000319410.9	TSL:1	c.982C>G	p.Pro328Ala	missense	Exon 8 of 15	ENSP00000325448.5
	KARS1	ENST00000566560.5	TSL:1	n.1012C>G		non_coding_transcript_exon	Exon 7 of 7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000468 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	D
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.29	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Pathogenic	4.4	H
PhyloP100		10
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-8.0	D
REVEL	Pathogenic	0.84
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.82
MutPred		0.87		Loss of catalytic residue at P300 (P = 0.0463)
MVP		0.98
MPC		0.49
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.96
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1555513082; hg19: chr16-75668088;