16-75641627-A-T

Variant names:

• chr16-75641627-A-T
• rs1555513622
• NM_005548.3:c.159T>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM2 BP4_Strong BP6_Moderate BP7

The NM_005548.3(KARS1):​c.159T>A​(p.Ala53Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: KARS1 NM_005548.3 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0940
• 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: G2P, Labcorp Genetics (formerly Invitae)
• 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: Likely_benign. The variant received -5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 16-75641627-A-T is Benign according to our data. Variant chr16-75641627-A-T is described in ClinVar as Likely_benign. ClinVar VariationId is 505559.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.094 with no splicing effect.

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.159T>A	p.Ala53Ala	synonymous	Exon 2 of 14	NP_005539.1	Q15046-1
	KARS1	NM_001130089.2		c.243T>A	p.Ala81Ala	synonymous	Exon 3 of 15	NP_001123561.1	Q15046-2
	KARS1	NM_001378148.1		c.-310T>A		5_prime_UTR	Exon 2 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.159T>A	p.Ala53Ala	synonymous	Exon 2 of 14	ENSP00000303043.3	Q15046-1
	KARS1	ENST00000319410.9	TSL:1	c.243T>A	p.Ala81Ala	synonymous	Exon 3 of 15	ENSP00000325448.5	Q15046-2
	KARS1	ENST00000566560.5	TSL:1	n.273T>A		non_coding_transcript_exon	Exon 2 of 7

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	2.6
DANN	Benign	0.29
PhyloP100		0.094
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs1555513622; hg19: chr16-75675525;