4-106316858-A-G

Variant names:

• chr4-106316858-A-G
• rs62318117
• NM_001142416.2:c.-26+264A>G

Variant summary

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

The NM_001142416.2(AIMP1):​c.-26+264A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0413 in 442,586 control chromosomes in the GnomAD database, including 495 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.037 (156 hom., cov: 32)
  • Exomes 𝑓: 0.043 (339 hom.)
• Consequence: AIMP1 NM_001142416.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.948
• Publications: 2 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: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia
• 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=-0.8).
• BP6: Variant 4-106316858-A-G is Benign according to our data. Variant chr4-106316858-A-G is described in ClinVar as Benign. ClinVar VariationId is 1283130.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0543 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001142416.2. 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_001142416.2	MANE Select	c.-26+264A>G		intron	N/A	NP_001135888.2	Q12904-1
	AIMP1	NM_001142415.2		c.-26+1222A>G		intron	N/A	NP_001135887.1	Q12904-1
	AIMP1	NM_004757.4		c.-26+514A>G		intron	N/A	NP_004748.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AIMP1	ENST00000672341.1	MANE Select	c.-26+264A>G		intron	N/A	ENSP00000500620.1	Q12904-1
	AIMP1	ENST00000394701.6	TSL:1	c.-162+264A>G		intron	N/A	ENSP00000378191.5	A0A8C8KIA0
	AIMP1	ENST00000672328.1		c.-3881A>G		5_prime_UTR_premature_start_codon_gain	Exon 1 of 7	ENSP00000500159.1	Q12904-1

Frequencies

GnomAD3 genomes AF: 0.0374 AC: 5690 AN: 152174 Hom.: 156 Cov.: 32

Gnomad AFR AF: 0.00989

Gnomad AMI AF: 0.112

Gnomad AMR AF: 0.0432

Gnomad ASJ AF: 0.0616

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00787

Gnomad FIN AF: 0.0361

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0558

Gnomad OTH AF: 0.0387

GnomAD4 exome AF: 0.0434 AC: 12592 AN: 290294 Hom.: 339 AF XY: 0.0426 AC XY: 6381 AN XY: 149670

African (AFR) AF: 0.00920 AC: 88 AN: 9564

American (AMR) AF: 0.0333 AC: 407 AN: 12210

Ashkenazi Jewish (ASJ) AF: 0.0629 AC: 600 AN: 9534

East Asian (EAS) AF: 0.00 AC: 0 AN: 22546

South Asian (SAS) AF: 0.0111 AC: 230 AN: 20744

European-Finnish (FIN) AF: 0.0346 AC: 679 AN: 19610

Middle Eastern (MID) AF: 0.0422 AC: 57 AN: 1350

European-Non Finnish (NFE) AF: 0.0555 AC: 9796 AN: 176480

Other (OTH) AF: 0.0403 AC: 735 AN: 18256

GnomAD4 genome AF: 0.0373 AC: 5686 AN: 152292 Hom.: 156 Cov.: 32 AF XY: 0.0363 AC XY: 2700 AN XY: 74458

African (AFR) AF: 0.00986 AC: 410 AN: 41576

American (AMR) AF: 0.0431 AC: 660 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0616 AC: 214 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.00767 AC: 37 AN: 4824

European-Finnish (FIN) AF: 0.0361 AC: 383 AN: 10614

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0558 AC: 3792 AN: 68004

Other (OTH) AF: 0.0383 AC: 81 AN: 2116

Alfa AF: 0.0131 Hom.: 10

Bravo AF: 0.0355

Asia WGS AF: 0.00606 AC: 21 AN: 3478

ClinVar

ClinVar submissions

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	-0.80
CADD	Benign	1.6
DANN	Benign	0.51
PhyloP100		-0.95
PromoterAI		0.038	Neutral
Mutation Taster		=100/0	polymorphism

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: rs62318117; hg19: chr4-107238015;