16-75627836-C-T

Variant names:

• chr16-75627836-C-T
• rs11505
• NM_005548.3:c.*59G>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.*59G>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 0.00318 in 962,462 control chromosomes in the GnomAD database, including 80 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (45 hom., cov: 33)
  • Exomes 𝑓: 0.0015 (35 hom.)
• Consequence: KARS1 NM_005548.3 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0200
• Publications: 4 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: Labcorp Genetics (formerly Invitae), G2P
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Charcot-Marie-Tooth disease recessive intermediate B

  Inheritance: Unknown, AR Classification: SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), 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=-0.72).
• BP6: Variant 16-75627836-C-T is Benign according to our data. Variant chr16-75627836-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 320621.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0122 (1860/152322) while in subpopulation AFR AF = 0.0415 (1726/41560). AF 95% confidence interval is 0.0399. There are 45 homozygotes in GnomAd4. There are 858 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 45 AR,Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005548.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KARS1	NM_005548.3	MANE Select	c.*59G>A		3_prime_UTR	Exon 14 of 14	NP_005539.1	Q15046-1
	KARS1	NM_001130089.2		c.*59G>A		3_prime_UTR	Exon 15 of 15	NP_001123561.1	Q15046-2
	KARS1	NM_001378148.1		c.*59G>A		3_prime_UTR	Exon 14 of 14	NP_001365077.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KARS1	ENST00000302445.8	TSL:1 MANE Select	c.*59G>A		3_prime_UTR	Exon 14 of 14	ENSP00000303043.3	Q15046-1
	KARS1	ENST00000319410.9	TSL:1	c.*59G>A		3_prime_UTR	Exon 15 of 15	ENSP00000325448.5	Q15046-2
	KARS1	ENST00000898534.1		c.*59G>A		3_prime_UTR	Exon 15 of 15	ENSP00000568593.1

Frequencies

GnomAD3 genomes AF: 0.0122 AC: 1855 AN: 152204 Hom.: 45 Cov.: 33

Gnomad AFR AF: 0.0416

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00681

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.0100

GnomAD4 exome AF: 0.00148 AC: 1202 AN: 810140 Hom.: 35 Cov.: 12 AF XY: 0.00123 AC XY: 527 AN XY: 429312

African (AFR) AF: 0.0418 AC: 856 AN: 20502

American (AMR) AF: 0.00323 AC: 142 AN: 43918

Ashkenazi Jewish (ASJ) AF: 0.0000453 AC: 1 AN: 22062

East Asian (EAS) AF: 0.00 AC: 0 AN: 36824

South Asian (SAS) AF: 0.000150 AC: 11 AN: 73252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52992

Middle Eastern (MID) AF: 0.00180 AC: 8 AN: 4436

European-Non Finnish (NFE) AF: 0.000112 AC: 58 AN: 517248

Other (OTH) AF: 0.00324 AC: 126 AN: 38906

GnomAD4 genome AF: 0.0122 AC: 1860 AN: 152322 Hom.: 45 Cov.: 33 AF XY: 0.0115 AC XY: 858 AN XY: 74498

African (AFR) AF: 0.0415 AC: 1726 AN: 41560

American (AMR) AF: 0.00680 AC: 104 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68026

Other (OTH) AF: 0.00992 AC: 21 AN: 2116

Alfa AF: 0.00376 Hom.: 4

Bravo AF: 0.0135

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	4.5
DANN	Benign	0.77
PhyloP100		0.020
Mutation Taster		=100/0	polymorphism (auto)

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: rs11505; hg19: chr16-75661734;