4-106316238-C-T

Variant names:

• chr4-106316238-C-T
• rs6814166
• NM_004757.4:c.-132C>T

Variant summary

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

The NM_004757.4(AIMP1):​c.-132C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.158 in 282,224 control chromosomes in the GnomAD database, including 3,920 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (1909 hom., cov: 31)
  • Exomes 𝑓: 0.16 (2011 hom.)
• Consequence: AIMP1 NM_004757.4 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.919

Genes affected

AIMP1 (HGNC:10648): (aminoacyl tRNA synthetase complex interacting multifunctional protein 1) The protein encoded by this gene is a cytokine that is specifically induced by apoptosis, and it is involved in the control of angiogenesis, inflammation, and wound healing. The release of this cytokine renders the tumor-associated vasculature sensitive to tumor necrosis factor. The precursor protein is identical to the p43 subunit, which is associated with the multi-tRNA synthetase complex, and it modulates aminoacylation activity of tRNA synthetase in normal cells. This protein is also involved in the stimulation of inflammatory responses after proteolytic cleavage in tumor cells. Multiple transcript variants encoding different isoforms have been found for this gene. A pseudogene has been identified on chromosome 20. [provided by RefSeq, Dec 2008]

TBCK (HGNC:28261): (TBC1 domain containing kinase) This gene encodes a protein that contains a protein kinase domain, a Rhodanase-like domain and the Tre-2/Bub2/Cdc16 (TBC) domain. The encoded protein is thought to play a role in actin organization, cell growth and cell proliferation by regulating the mammalian target of the rapamycin (mTOR) signaling pathway. This protein may also be involved in the transcriptional regulation of the components of the mTOR complex. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2014]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 4-106316238-C-T is Benign according to our data. Variant chr4-106316238-C-T is described in ClinVar as [Benign]. Clinvar id is 1272300.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.237 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBCK	NM_001163435.3	c.-337G>A		upstream_gene_variant		ENST00000394708.7	NP_001156907.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBCK	ENST00000394708.7	c.-337G>A		upstream_gene_variant		1	NM_001163435.3	ENSP00000378198.2

Frequencies

GnomAD3 genomes AF: 0.154 AC: 23441 AN: 151880 Hom.: 1909 Cov.: 31

Gnomad AFR AF: 0.115

Gnomad AMI AF: 0.258

Gnomad AMR AF: 0.118

Gnomad ASJ AF: 0.123

Gnomad EAS AF: 0.137

Gnomad SAS AF: 0.251

Gnomad FIN AF: 0.198

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.175

Gnomad OTH AF: 0.142

GnomAD4 exome AF: 0.163 AC: 21185 AN: 130226 Hom.: 2011 Cov.: 0 AF XY: 0.165 AC XY: 11129 AN XY: 67598

Gnomad4 AFR exome AF: 0.106 AC: 472 AN: 4464

Gnomad4 AMR exome AF: 0.116 AC: 565 AN: 4886

Gnomad4 ASJ exome AF: 0.115 AC: 541 AN: 4714

Gnomad4 EAS exome AF: 0.174 AC: 1632 AN: 9376

Gnomad4 SAS exome AF: 0.219 AC: 1930 AN: 8796

Gnomad4 FIN exome AF: 0.193 AC: 1654 AN: 8568

Gnomad4 NFE exome AF: 0.163 AC: 13081 AN: 80374

Gnomad4 Remaining exome AF: 0.147 AC: 1224 AN: 8336

GnomAD4 genome AF: 0.154 AC: 23451 AN: 151998 Hom.: 1909 Cov.: 31 AF XY: 0.156 AC XY: 11557 AN XY: 74254

Gnomad4 AFR AF: 0.116 AC: 0.115626 AN: 0.115626

Gnomad4 AMR AF: 0.118 AC: 0.117989 AN: 0.117989

Gnomad4 ASJ AF: 0.123 AC: 0.122984 AN: 0.122984

Gnomad4 EAS AF: 0.137 AC: 0.13709 AN: 0.13709

Gnomad4 SAS AF: 0.249 AC: 0.248857 AN: 0.248857

Gnomad4 FIN AF: 0.198 AC: 0.19782 AN: 0.19782

Gnomad4 NFE AF: 0.175 AC: 0.174684 AN: 0.174684

Gnomad4 OTH AF: 0.142 AC: 0.14218 AN: 0.14218

Alfa AF: 0.159 Hom.: 2534

Bravo AF: 0.145

Asia WGS AF: 0.212 AC: 735 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 10, 2018

GeneDx

Significance: 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	-0.77
CADD	Benign	13
DANN	Benign	0.78
Mutation Taster		=300/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs6814166; hg19: chr4-107237395;