NM_005548.3:c.63-1406T>C

Variant names:

• chr16-75643129-A-G
• rs3784929
• NM_005548.3:c.63-1406T>C

Variant summary

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

The NM_005548.3(KARS1):​c.63-1406T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.302 in 152,106 control chromosomes in the GnomAD database, including 10,791 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 0.30 (10791 hom., cov: 32)
• Consequence: KARS1 NM_005548.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.118
• Publications: 15 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.74 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.63-1406T>C		intron	N/A	NP_005539.1	Q15046-1
	KARS1	NM_001130089.2		c.146+1154T>C		intron	N/A	NP_001123561.1	Q15046-2
	KARS1	NM_001378148.1		c.-406-1406T>C		intron	N/A	NP_001365077.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KARS1	ENST00000302445.8	TSL:1 MANE Select	c.63-1406T>C		intron	N/A	ENSP00000303043.3	Q15046-1
	KARS1	ENST00000319410.9	TSL:1	c.146+1154T>C		intron	N/A	ENSP00000325448.5	Q15046-2
	KARS1	ENST00000566560.5	TSL:1	n.177-1406T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.302 AC: 45861 AN: 151988 Hom.: 10753 Cov.: 32

Gnomad AFR AF: 0.581

Gnomad AMI AF: 0.166

Gnomad AMR AF: 0.372

Gnomad ASJ AF: 0.210

Gnomad EAS AF: 0.760

Gnomad SAS AF: 0.416

Gnomad FIN AF: 0.129

Gnomad MID AF: 0.161

Gnomad NFE AF: 0.108

Gnomad OTH AF: 0.265

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

GnomAD4 genome AF: 0.302 AC: 45963 AN: 152106 Hom.: 10791 Cov.: 32 AF XY: 0.309 AC XY: 22993 AN XY: 74372

African (AFR) AF: 0.582 AC: 24111 AN: 41444

American (AMR) AF: 0.373 AC: 5688 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.210 AC: 729 AN: 3470

East Asian (EAS) AF: 0.760 AC: 3929 AN: 5170

South Asian (SAS) AF: 0.414 AC: 1997 AN: 4824

European-Finnish (FIN) AF: 0.129 AC: 1366 AN: 10606

Middle Eastern (MID) AF: 0.170 AC: 50 AN: 294

European-Non Finnish (NFE) AF: 0.108 AC: 7378 AN: 68010

Other (OTH) AF: 0.267 AC: 564 AN: 2112

Alfa AF: 0.177 Hom.: 2578

Bravo AF: 0.335

Asia WGS AF: 0.585 AC: 2029 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	5.0
DANN	Benign	0.56
PhyloP100		0.12
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: rs3784929; hg19: chr16-75677027;