NM_004757.4:c.-132C>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
• Publications: 10 publications found

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]

TBCK Gene-Disease associations (from GenCC):

• hypotonia, infantile, with psychomotor retardation and characteristic facies 3

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• syndromic complex neurodevelopmental disorder

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen

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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004757.4. 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
	AIMP1	NM_004757.4		c.-132C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 7	NP_004748.2
	AIMP1	NM_004757.4		c.-132C>T		5_prime_UTR	Exon 1 of 7	NP_004748.2
	TBCK	NM_001163436.4		c.-30+310G>A		intron	N/A	NP_001156908.2	Q8TEA7-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AIMP1	ENST00000358008.7	TSL:2	c.-132C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 7	ENSP00000350699.3	Q12904-1
	TBCK	ENST00000885939.1		c.-349G>A		5_prime_UTR	Exon 1 of 26	ENSP00000555998.1
	TBCK	ENST00000967907.1		c.-337G>A		5_prime_UTR	Exon 1 of 23	ENSP00000637966.1

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

African (AFR) AF: 0.106 AC: 472 AN: 4464

American (AMR) AF: 0.116 AC: 565 AN: 4886

Ashkenazi Jewish (ASJ) AF: 0.115 AC: 541 AN: 4714

East Asian (EAS) AF: 0.174 AC: 1632 AN: 9376

South Asian (SAS) AF: 0.219 AC: 1930 AN: 8796

European-Finnish (FIN) AF: 0.193 AC: 1654 AN: 8568

Middle Eastern (MID) AF: 0.121 AC: 86 AN: 712

European-Non Finnish (NFE) AF: 0.163 AC: 13081 AN: 80374

Other (OTH) 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

African (AFR) AF: 0.116 AC: 4792 AN: 41444

American (AMR) AF: 0.118 AC: 1805 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.123 AC: 427 AN: 3472

East Asian (EAS) AF: 0.137 AC: 703 AN: 5128

South Asian (SAS) AF: 0.249 AC: 1197 AN: 4810

European-Finnish (FIN) AF: 0.198 AC: 2087 AN: 10550

Middle Eastern (MID) AF: 0.102 AC: 30 AN: 294

European-Non Finnish (NFE) AF: 0.175 AC: 11875 AN: 67980

Other (OTH) AF: 0.142 AC: 300 AN: 2110

Alfa AF: 0.159 Hom.: 2534

Bravo AF: 0.145

Asia WGS AF: 0.212 AC: 735 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: 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	-0.77
CADD	Benign	13
DANN	Benign	0.78
PhyloP100		0.92
PromoterAI		-0.44	Neutral
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

Other links and lift over

dbSNP: rs6814166; hg19: chr4-107237395;