rs2233805

Variant names:

• chr16-75647244-T-C
• rs2233805
• NM_005548.3:c.62+334A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005548.3(KARS1):​c.62+334A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.095 in 152,306 control chromosomes in the GnomAD database, including 1,247 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.095 (1247 hom., cov: 32)
• Consequence: KARS1 NM_005548.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.618
• Publications: 5 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.229 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KARS1	NM_005548.3	c.62+334A>G		intron_variant	Intron 1 of 13	ENST00000302445.8	NP_005539.1
KARS1	NM_001130089.2	c.-35+334A>G		intron_variant	Intron 1 of 14		NP_001123561.1
KARS1	NM_001378148.1	c.-407+220A>G		intron_variant	Intron 1 of 13		NP_001365077.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KARS1	ENST00000302445.8	c.62+334A>G		intron_variant	Intron 1 of 13	1	NM_005548.3	ENSP00000303043.3

Frequencies

GnomAD3 genomes AF: 0.0950 AC: 14452 AN: 152188 Hom.: 1245 Cov.: 32

Gnomad AFR AF: 0.233

Gnomad AMI AF: 0.0219

Gnomad AMR AF: 0.0396

Gnomad ASJ AF: 0.0421

Gnomad EAS AF: 0.0146

Gnomad SAS AF: 0.0499

Gnomad FIN AF: 0.0651

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0421

Gnomad OTH AF: 0.0664

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0950 AC: 14471 AN: 152306 Hom.: 1247 Cov.: 32 AF XY: 0.0923 AC XY: 6875 AN XY: 74492

African (AFR) AF: 0.233 AC: 9674 AN: 41528

American (AMR) AF: 0.0396 AC: 606 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0421 AC: 146 AN: 3470

East Asian (EAS) AF: 0.0143 AC: 74 AN: 5188

South Asian (SAS) AF: 0.0501 AC: 242 AN: 4830

European-Finnish (FIN) AF: 0.0651 AC: 692 AN: 10630

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.0421 AC: 2867 AN: 68030

Other (OTH) AF: 0.0658 AC: 139 AN: 2114

Alfa AF: 0.0585 Hom.: 1862

Bravo AF: 0.0991

Asia WGS AF: 0.0510 AC: 179 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	2.3
DANN	Benign	0.34
PhyloP100		-0.62
PromoterAI		0.041	Neutral
Mutation Taster		=100/0	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: rs2233805; hg19: chr16-75681142;