chr16-75627869-G-C

Variant names:

• chr16-75627869-G-C
• rs78654839
• NM_005548.3:c.*26C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_005548.3(KARS1):​c.*26C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0088 in 1,293,254 control chromosomes in the GnomAD database, including 95 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0076 (15 hom., cov: 33)
  • Exomes 𝑓: 0.0090 (80 hom.)
• Consequence: KARS1 NM_005548.3 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.271
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 16-75627869-G-C is Benign according to our data. Variant chr16-75627869-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 320623.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00761 (1159/152348) while in subpopulation NFE AF = 0.00917 (624/68040). AF 95% confidence interval is 0.00858. There are 15 homozygotes in GnomAd4. There are 608 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 15 AR,Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KARS1	NM_005548.3	c.*26C>G		3_prime_UTR_variant	Exon 14 of 14	ENST00000302445.8	NP_005539.1
KARS1	NM_001130089.2	c.*26C>G		3_prime_UTR_variant	Exon 15 of 15		NP_001123561.1
KARS1	NM_001378148.1	c.*26C>G		3_prime_UTR_variant	Exon 14 of 14		NP_001365077.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KARS1	ENST00000302445.8	c.*26C>G		3_prime_UTR_variant	Exon 14 of 14	1	NM_005548.3	ENSP00000303043.3

Frequencies

GnomAD3 genomes AF: 0.00761 AC: 1159 AN: 152230 Hom.: 15 Cov.: 33

Gnomad AFR AF: 0.00135

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00399

Gnomad ASJ AF: 0.0107

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.0337

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00917

Gnomad OTH AF: 0.00860

GnomAD2 exomes AF: 0.00839 AC: 2109 AN: 251336 AF XY: 0.00845

Gnomad AFR exome AF: 0.00129

Gnomad AMR exome AF: 0.00312

Gnomad ASJ exome AF: 0.0111

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0337

Gnomad NFE exome AF: 0.00903

Gnomad OTH exome AF: 0.00913

GnomAD4 exome AF: 0.00896 AC: 10217 AN: 1140906 Hom.: 80 Cov.: 16 AF XY: 0.00872 AC XY: 5090 AN XY: 583448

African (AFR) AF: 0.00156 AC: 41 AN: 26298

American (AMR) AF: 0.00284 AC: 126 AN: 44376

Ashkenazi Jewish (ASJ) AF: 0.0110 AC: 266 AN: 24136

East Asian (EAS) AF: 0.00 AC: 0 AN: 38276

South Asian (SAS) AF: 0.00182 AC: 145 AN: 79804

European-Finnish (FIN) AF: 0.0346 AC: 1843 AN: 53294

Middle Eastern (MID) AF: 0.00637 AC: 33 AN: 5184

European-Non Finnish (NFE) AF: 0.00880 AC: 7217 AN: 819862

Other (OTH) AF: 0.0110 AC: 546 AN: 49676

GnomAD4 genome AF: 0.00761 AC: 1159 AN: 152348 Hom.: 15 Cov.: 33 AF XY: 0.00816 AC XY: 608 AN XY: 74498

African (AFR) AF: 0.00135 AC: 56 AN: 41588

American (AMR) AF: 0.00399 AC: 61 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0107 AC: 37 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4828

European-Finnish (FIN) AF: 0.0337 AC: 357 AN: 10608

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00917 AC: 624 AN: 68040

Other (OTH) AF: 0.00851 AC: 18 AN: 2116

Alfa AF: 0.00632 Hom.: 1

Bravo AF: 0.00526

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 17, 2018

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	-0.83
CADD	Benign	2.7
DANN	Benign	0.48
PhyloP100		-0.27
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

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: rs78654839; hg19: chr16-75661767;