chr16-75627905-G-C

Variant names:

• chr16-75627905-G-C
• rs6834
• NM_005548.3:c.1784C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005548.3(KARS1):​c.1784C>G​(p.Thr595Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0539 in 1,578,048 control chromosomes in the GnomAD database, including 5,488 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (2288 hom., cov: 33)
  • Exomes 𝑓: 0.047 (3200 hom.)
• Consequence: KARS1 NM_005548.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 6.42
• Publications: 18 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 (MetaRNN=0.003862083).
• BP6: Variant 16-75627905-G-C is Benign according to our data. Variant chr16-75627905-G-C is described in ClinVar as Benign. ClinVar VariationId is 226682.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.317 is higher than 0.05.

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.1784C>G	p.Thr595Ser	missense	Exon 14 of 14	NP_005539.1	Q15046-1
	KARS1	NM_001130089.2		c.1868C>G	p.Thr623Ser	missense	Exon 15 of 15	NP_001123561.1	Q15046-2
	KARS1	NM_001378148.1		c.1316C>G	p.Thr439Ser	missense	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.1784C>G	p.Thr595Ser	missense	Exon 14 of 14	ENSP00000303043.3	Q15046-1
	KARS1	ENST00000319410.9	TSL:1	c.1868C>G	p.Thr623Ser	missense	Exon 15 of 15	ENSP00000325448.5	Q15046-2
	KARS1	ENST00000898534.1		c.1898C>G	p.Thr633Ser	missense	Exon 15 of 15	ENSP00000568593.1

Frequencies

GnomAD3 genomes AF: 0.119 AC: 18163 AN: 152128 Hom.: 2283 Cov.: 33

Gnomad AFR AF: 0.322

Gnomad AMI AF: 0.0219

Gnomad AMR AF: 0.0499

Gnomad ASJ AF: 0.0421

Gnomad EAS AF: 0.00519

Gnomad SAS AF: 0.0547

Gnomad FIN AF: 0.0644

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0405

Gnomad OTH AF: 0.0828

GnomAD2 exomes AF: 0.0584 AC: 14678 AN: 251416 AF XY: 0.0539

Gnomad AFR exome AF: 0.328

Gnomad AMR exome AF: 0.0265

Gnomad ASJ exome AF: 0.0392

Gnomad EAS exome AF: 0.00511

Gnomad FIN exome AF: 0.0652

Gnomad NFE exome AF: 0.0405

Gnomad OTH exome AF: 0.0482

GnomAD4 exome AF: 0.0468 AC: 66796 AN: 1425802 Hom.: 3200 Cov.: 26 AF XY: 0.0460 AC XY: 32736 AN XY: 711752

African (AFR) AF: 0.330 AC: 10633 AN: 32228

American (AMR) AF: 0.0290 AC: 1297 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.0414 AC: 1073 AN: 25918

East Asian (EAS) AF: 0.00539 AC: 213 AN: 39534

South Asian (SAS) AF: 0.0520 AC: 4442 AN: 85484

European-Finnish (FIN) AF: 0.0677 AC: 3615 AN: 53390

Middle Eastern (MID) AF: 0.0471 AC: 267 AN: 5664

European-Non Finnish (NFE) AF: 0.0386 AC: 41691 AN: 1079722

Other (OTH) AF: 0.0603 AC: 3565 AN: 59168

GnomAD4 genome AF: 0.120 AC: 18201 AN: 152246 Hom.: 2288 Cov.: 33 AF XY: 0.116 AC XY: 8656 AN XY: 74444

African (AFR) AF: 0.322 AC: 13360 AN: 41500

American (AMR) AF: 0.0498 AC: 762 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0421 AC: 146 AN: 3472

East Asian (EAS) AF: 0.00501 AC: 26 AN: 5194

South Asian (SAS) AF: 0.0545 AC: 263 AN: 4824

European-Finnish (FIN) AF: 0.0644 AC: 683 AN: 10604

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.0405 AC: 2757 AN: 68036

Other (OTH) AF: 0.0819 AC: 173 AN: 2112

Alfa AF: 0.0430 Hom.: 109

Bravo AF: 0.127

TwinsUK AF: 0.0334 AC: 124

ALSPAC AF: 0.0415 AC: 160

ESP6500AA AF: 0.324 AC: 1426

ESP6500EA AF: 0.0405 AC: 348

ExAC AF: 0.0657 AC: 7980

Asia WGS AF: 0.0550 AC: 191 AN: 3478

EpiCase AF: 0.0399

EpiControl AF: 0.0351

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Autosomal recessive nonsyndromic hearing loss 89 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.20
Eigen_PC	Benign	0.057
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.51	T
MetaRNN	Benign	0.0039	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.55	N
PhyloP100		6.4
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.11	N
REVEL	Uncertain	0.31
Sift	Benign	0.18	T
Sift4G	Benign	0.079	T
Polyphen		0.021	B
Vest4		0.090
MutPred		0.046		Loss of glycosylation at T595 (P = 0.049)
MPC		0.084
ClinPred		0.016	T
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.056
gMVP		0.66
Mutation Taster		=96/4	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: rs6834; hg19: chr16-75661803; COSMIC: COSV56692024; COSMIC: COSV56692024;