NM_005548.3:c.1696-21G>A

Variant names:

• chr16-75628014-C-T
• rs188921559
• NM_005548.3:c.1696-21G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_005548.3(KARS1):​c.1696-21G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00491 in 1,415,436 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0035 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0051 (25 hom.)
• Consequence: KARS1 NM_005548.3 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.16
• 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 16-75628014-C-T is Benign according to our data. Variant chr16-75628014-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 1206517.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00352 (536/152274) while in subpopulation NFE AF = 0.00588 (400/68028). AF 95% confidence interval is 0.0054. There are 3 homozygotes in GnomAd4. There are 246 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR,Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KARS1	NM_005548.3	c.1696-21G>A		intron_variant	Intron 13 of 13	ENST00000302445.8	NP_005539.1
KARS1	NM_001130089.2	c.1780-21G>A		intron_variant	Intron 14 of 14		NP_001123561.1
KARS1	NM_001378148.1	c.1228-21G>A		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.1696-21G>A		intron_variant	Intron 13 of 13	1	NM_005548.3	ENSP00000303043.3

Frequencies

GnomAD3 genomes AF: 0.00352 AC: 536 AN: 152156 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.00150

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.00386

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00588

Gnomad OTH AF: 0.00334

GnomAD2 exomes AF: 0.00281 AC: 701 AN: 249792 AF XY: 0.00285

Gnomad AFR exome AF: 0.00142

Gnomad AMR exome AF: 0.00191

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000231

Gnomad NFE exome AF: 0.00513

Gnomad OTH exome AF: 0.00359

GnomAD4 exome AF: 0.00508 AC: 6420 AN: 1263162 Hom.: 25 Cov.: 18 AF XY: 0.00494 AC XY: 3159 AN XY: 639210

African (AFR) AF: 0.00126 AC: 37 AN: 29364

American (AMR) AF: 0.00180 AC: 80 AN: 44494

Ashkenazi Jewish (ASJ) AF: 0.000200 AC: 5 AN: 24948

East Asian (EAS) AF: 0.00 AC: 0 AN: 38762

South Asian (SAS) AF: 0.000243 AC: 20 AN: 82286

European-Finnish (FIN) AF: 0.000319 AC: 17 AN: 53306

Middle Eastern (MID) AF: 0.000739 AC: 4 AN: 5414

European-Non Finnish (NFE) AF: 0.00652 AC: 6069 AN: 930834

Other (OTH) AF: 0.00350 AC: 188 AN: 53754

GnomAD4 genome AF: 0.00352 AC: 536 AN: 152274 Hom.: 3 Cov.: 33 AF XY: 0.00330 AC XY: 246 AN XY: 74460

African (AFR) AF: 0.00149 AC: 62 AN: 41552

American (AMR) AF: 0.00386 AC: 59 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.000471 AC: 5 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00588 AC: 400 AN: 68028

Other (OTH) AF: 0.00331 AC: 7 AN: 2116

Alfa AF: 0.00348 Hom.: 0

Bravo AF: 0.00390

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jul 28, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.34
DANN	Benign	0.31
PhyloP100		-1.2
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs188921559; hg19: chr16-75661912;