16-75627862-C-T

Variant names:

• chr16-75627862-C-T
• rs111679674
• NM_005548.3:c.*33G>A

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.*33G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00929 in 1,212,610 control chromosomes in the GnomAD database, including 101 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0083 (19 hom., cov: 33)
  • Exomes 𝑓: 0.0094 (82 hom.)
• Consequence: KARS1 NM_005548.3 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.473
• Publications: 1 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=-0.88).
• BP6: Variant 16-75627862-C-T is Benign according to our data. Variant chr16-75627862-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 1218463.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 = 0.0083 (1264/152298) while in subpopulation NFE AF = 0.00944 (642/68022). AF 95% confidence interval is 0.00883. There are 19 homozygotes in GnomAd4. There are 660 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 19 AR,Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KARS1	NM_005548.3	c.*33G>A		3_prime_UTR_variant	Exon 14 of 14	ENST00000302445.8	NP_005539.1
KARS1	NM_001130089.2	c.*33G>A		3_prime_UTR_variant	Exon 15 of 15		NP_001123561.1
KARS1	NM_001378148.1	c.*33G>A		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.*33G>A		3_prime_UTR_variant	Exon 14 of 14	1	NM_005548.3	ENSP00000303043.3

Frequencies

GnomAD3 genomes AF: 0.00831 AC: 1264 AN: 152180 Hom.: 19 Cov.: 33

Gnomad AFR AF: 0.00142

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00426

Gnomad ASJ AF: 0.0325

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.0337

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00944

Gnomad OTH AF: 0.00909

GnomAD2 exomes AF: 0.00947 AC: 2379 AN: 251294 AF XY: 0.00956

Gnomad AFR exome AF: 0.00136

Gnomad AMR exome AF: 0.00327

Gnomad ASJ exome AF: 0.0292

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0336

Gnomad NFE exome AF: 0.00953

Gnomad OTH exome AF: 0.0117

GnomAD4 exome AF: 0.00943 AC: 9999 AN: 1060312 Hom.: 82 Cov.: 15 AF XY: 0.00914 AC XY: 4991 AN XY: 546128

African (AFR) AF: 0.00173 AC: 43 AN: 24798

American (AMR) AF: 0.00294 AC: 130 AN: 44270

Ashkenazi Jewish (ASJ) AF: 0.0305 AC: 722 AN: 23686

East Asian (EAS) AF: 0.0000528 AC: 2 AN: 37888

South Asian (SAS) AF: 0.00208 AC: 163 AN: 78214

European-Finnish (FIN) AF: 0.0345 AC: 1840 AN: 53264

Middle Eastern (MID) AF: 0.00737 AC: 37 AN: 5022

European-Non Finnish (NFE) AF: 0.00867 AC: 6470 AN: 746070

Other (OTH) AF: 0.0126 AC: 592 AN: 47100

GnomAD4 genome AF: 0.00830 AC: 1264 AN: 152298 Hom.: 19 Cov.: 33 AF XY: 0.00886 AC XY: 660 AN XY: 74476

African (AFR) AF: 0.00142 AC: 59 AN: 41572

American (AMR) AF: 0.00425 AC: 65 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0325 AC: 113 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5194

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4828

European-Finnish (FIN) AF: 0.0337 AC: 358 AN: 10612

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

European-Non Finnish (NFE) AF: 0.00944 AC: 642 AN: 68022

Other (OTH) AF: 0.00900 AC: 19 AN: 2112

Alfa AF: 0.0112 Hom.: 3

Bravo AF: 0.00596

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

Jul 11, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	2.1
DANN	Benign	0.71
PhyloP100		-0.47
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: rs111679674; hg19: chr16-75661760;