chr16-75640790-G-A

Variant names:

• chr16-75640790-G-A
• rs8053257
• NM_005548.3:c.223-441C>T

Variant summary

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

The NM_005548.3(KARS1):​c.223-441C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.178 in 152,216 control chromosomes in the GnomAD database, including 5,027 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 0.18 (5027 hom., cov: 32)
• Consequence: KARS1 NM_005548.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.272
• Publications: 10 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=-0.82).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.471 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KARS1	NM_005548.3	MANE Select	c.223-441C>T		intron	N/A	NP_005539.1
	KARS1	NM_001130089.2		c.307-441C>T		intron	N/A	NP_001123561.1
	KARS1	NM_001378148.1		c.-246-441C>T		intron	N/A	NP_001365077.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KARS1	ENST00000302445.8	TSL:1 MANE Select	c.223-441C>T		intron	N/A	ENSP00000303043.3
	KARS1	ENST00000319410.9	TSL:1	c.307-441C>T		intron	N/A	ENSP00000325448.5
	KARS1	ENST00000566560.5	TSL:1	n.337-441C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.178 AC: 27012 AN: 152098 Hom.: 5019 Cov.: 32

Gnomad AFR AF: 0.477

Gnomad AMI AF: 0.0592

Gnomad AMR AF: 0.0794

Gnomad ASJ AF: 0.0737

Gnomad EAS AF: 0.0337

Gnomad SAS AF: 0.107

Gnomad FIN AF: 0.0711

Gnomad MID AF: 0.0949

Gnomad NFE AF: 0.0590

Gnomad OTH AF: 0.134

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

GnomAD4 genome AF: 0.178 AC: 27056 AN: 152216 Hom.: 5027 Cov.: 32 AF XY: 0.173 AC XY: 12854 AN XY: 74440

African (AFR) AF: 0.477 AC: 19770 AN: 41486

American (AMR) AF: 0.0792 AC: 1212 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0737 AC: 256 AN: 3472

East Asian (EAS) AF: 0.0335 AC: 174 AN: 5188

South Asian (SAS) AF: 0.106 AC: 512 AN: 4822

European-Finnish (FIN) AF: 0.0711 AC: 754 AN: 10610

Middle Eastern (MID) AF: 0.102 AC: 30 AN: 294

European-Non Finnish (NFE) AF: 0.0590 AC: 4013 AN: 68026

Other (OTH) AF: 0.133 AC: 281 AN: 2112

Alfa AF: 0.0888 Hom.: 2386

Bravo AF: 0.190

Asia WGS AF: 0.117 AC: 406 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.8
DANN	Benign	0.40
PhyloP100		-0.27
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: rs8053257; hg19: chr16-75674688;