16-75627995-T-G

Variant names:

• chr16-75627995-T-G
• rs1299524768
• NM_005548.3:c.1696-2A>C

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_005548.3(KARS1):​c.1696-2A>C variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000212 in 1,413,368 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: KARS1 NM_005548.3 splice_acceptor, intron
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.21
• 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 8 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.15050167 fraction of the gene.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-75627995-T-G is Pathogenic according to our data. Variant chr16-75627995-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 1675188.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KARS1	NM_005548.3	c.1696-2A>C		splice_acceptor_variant, intron_variant	Intron 13 of 13	ENST00000302445.8	NP_005539.1
KARS1	NM_001130089.2	c.1780-2A>C		splice_acceptor_variant, intron_variant	Intron 14 of 14		NP_001123561.1
KARS1	NM_001378148.1	c.1228-2A>C		splice_acceptor_variant, intron_variant	Intron 13 of 13		NP_001365077.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KARS1	ENST00000302445.8	c.1696-2A>C		splice_acceptor_variant, intron_variant	Intron 13 of 13	1	NM_005548.3	ENSP00000303043.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250412 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000887

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000212 AC: 3 AN: 1413368 Hom.: 0 Cov.: 24 AF XY: 0.00000142 AC XY: 1 AN XY: 706262

African (AFR) AF: 0.00 AC: 0 AN: 32414

American (AMR) AF: 0.00 AC: 0 AN: 44676

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25860

East Asian (EAS) AF: 0.00 AC: 0 AN: 39462

South Asian (SAS) AF: 0.00 AC: 0 AN: 85286

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53396

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5672

European-Non Finnish (NFE) AF: 0.00000281 AC: 3 AN: 1067916

Other (OTH) AF: 0.00 AC: 0 AN: 58686

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 89 Pathogenic:1

Feb 14, 2022

Institute of Human Genetics, University Hospital Muenster

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG categories: PVS1,PM2,PP3 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	30
DANN	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.98	D
PhyloP100		7.2
GERP RS		6.0
Mutation Taster		=2/98	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.99		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1299524768; hg19: chr16-75661893;