rs16941301

Variant names:

• chr16-75631596-G-A
• rs16941301
• NM_005548.3:c.1079-7C>T

Your query was ambiguous. Multiple possible variants found:

• chr16-75631596-G-A
• chr16-75631596-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005548.3(KARS1):​c.1079-7C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0218 in 1,614,092 control chromosomes in the GnomAD database, including 672 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.032 (119 hom., cov: 32)
  • Exomes 𝑓: 0.021 (553 hom.)
• Consequence: KARS1 NM_005548.3 splice_region, intron
• Scores: Splicing: ADA: 0.0002188
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.551
• Publications: 7 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 16-75631596-G-A is Benign according to our data. Variant chr16-75631596-G-A is described in ClinVar as Benign. ClinVar VariationId is 226678.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0649 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KARS1	NM_005548.3	c.1079-7C>T		splice_region_variant, intron_variant	Intron 8 of 13	ENST00000302445.8	NP_005539.1
KARS1	NM_001130089.2	c.1163-7C>T		splice_region_variant, intron_variant	Intron 9 of 14		NP_001123561.1
KARS1	NM_001378148.1	c.611-7C>T		splice_region_variant, intron_variant	Intron 8 of 13		NP_001365077.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KARS1	ENST00000302445.8	c.1079-7C>T		splice_region_variant, intron_variant	Intron 8 of 13	1	NM_005548.3	ENSP00000303043.3

Frequencies

GnomAD3 genomes AF: 0.0322 AC: 4896 AN: 152168 Hom.: 118 Cov.: 32

Gnomad AFR AF: 0.0670

Gnomad AMI AF: 0.0373

Gnomad AMR AF: 0.0188

Gnomad ASJ AF: 0.0314

Gnomad EAS AF: 0.0302

Gnomad SAS AF: 0.0578

Gnomad FIN AF: 0.00593

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.0163

Gnomad OTH AF: 0.0320

GnomAD2 exomes AF: 0.0268 AC: 6734 AN: 251356 AF XY: 0.0281

Gnomad AFR exome AF: 0.0690

Gnomad AMR exome AF: 0.0144

Gnomad ASJ exome AF: 0.0304

Gnomad EAS exome AF: 0.0261

Gnomad FIN exome AF: 0.00462

Gnomad NFE exome AF: 0.0175

Gnomad OTH exome AF: 0.0231

GnomAD4 exome AF: 0.0207 AC: 30231 AN: 1461806 Hom.: 553 Cov.: 34 AF XY: 0.0221 AC XY: 16054 AN XY: 727210

African (AFR) AF: 0.0723 AC: 2421 AN: 33470

American (AMR) AF: 0.0157 AC: 701 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0316 AC: 826 AN: 26136

East Asian (EAS) AF: 0.0259 AC: 1027 AN: 39700

South Asian (SAS) AF: 0.0661 AC: 5699 AN: 86254

European-Finnish (FIN) AF: 0.00594 AC: 317 AN: 53410

Middle Eastern (MID) AF: 0.0511 AC: 295 AN: 5768

European-Non Finnish (NFE) AF: 0.0156 AC: 17397 AN: 1111952

Other (OTH) AF: 0.0256 AC: 1548 AN: 60392

GnomAD4 genome AF: 0.0322 AC: 4900 AN: 152286 Hom.: 119 Cov.: 32 AF XY: 0.0319 AC XY: 2377 AN XY: 74472

African (AFR) AF: 0.0670 AC: 2782 AN: 41532

American (AMR) AF: 0.0188 AC: 287 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0314 AC: 109 AN: 3472

East Asian (EAS) AF: 0.0303 AC: 157 AN: 5186

South Asian (SAS) AF: 0.0572 AC: 276 AN: 4824

European-Finnish (FIN) AF: 0.00593 AC: 63 AN: 10622

Middle Eastern (MID) AF: 0.0612 AC: 18 AN: 294

European-Non Finnish (NFE) AF: 0.0163 AC: 1107 AN: 68026

Other (OTH) AF: 0.0317 AC: 67 AN: 2114

Alfa AF: 0.0214 Hom.: 86

Bravo AF: 0.0342

Asia WGS AF: 0.0660 AC: 228 AN: 3478

EpiCase AF: 0.0172

EpiControl AF: 0.0177

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 18, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 23, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:2

Aug 03, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Nov 24, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

1163-7C>T in intron 9 of KARS: This variant is not expected to have clinical sig nificance because it has been identified in 6.0% (263/4396) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; dbSNP rs16941301). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	8.3
DANN	Benign	0.61
PhyloP100		0.55
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00022
dbscSNV1_RF	Benign	0.0060
SpliceAI score (max)		0.020		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: rs16941301; hg19: chr16-75665494; COSMIC: COSV56692486; COSMIC: COSV56692486;