rs113844295

Variant names:

• chr4-106328162-A-G
• rs113844295
• NM_001142416.2:c.310A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004757.4(AIMP1):​c.310A>G​(p.Thr104Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00188 in 1,613,570 control chromosomes in the GnomAD database, including 57 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T104T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0097 (21 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (36 hom.)
• Consequence: AIMP1 NM_004757.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.564
• Publications: 5 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]

AIMP1 Gene-Disease associations (from GenCC):

• hypomyelinating leukodystrophy 3

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, Orphanet
• autosomal recessive non-syndromic intellectual disability

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0024947822).
• BP6: Variant 4-106328162-A-G is Benign according to our data. Variant chr4-106328162-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 446035.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00974 (1483/152316) while in subpopulation AFR AF = 0.034 (1415/41562). AF 95% confidence interval is 0.0326. There are 21 homozygotes in GnomAd4. There are 706 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 21 AR gene

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_001142416.2	MANE Select	c.310A>G	p.Thr104Ala	missense	Exon 4 of 7	NP_001135888.2
	AIMP1	NM_001142415.2		c.310A>G	p.Thr104Ala	missense	Exon 4 of 7	NP_001135887.1
	AIMP1	NM_004757.4		c.310A>G	p.Thr104Ala	missense	Exon 4 of 7	NP_004748.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AIMP1	ENST00000672341.1	MANE Select	c.310A>G	p.Thr104Ala	missense	Exon 4 of 7	ENSP00000500620.1
	AIMP1	ENST00000394701.6	TSL:1	c.40A>G	p.Thr14Ala	missense	Exon 3 of 6	ENSP00000378191.5
	AIMP1	ENST00000358008.7	TSL:2	c.310A>G	p.Thr104Ala	missense	Exon 4 of 7	ENSP00000350699.3

Frequencies

GnomAD3 genomes AF: 0.00973 AC: 1481 AN: 152198 Hom.: 21 Cov.: 32

Gnomad AFR AF: 0.0341

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000413

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00672

GnomAD2 exomes AF: 0.00249 AC: 625 AN: 251090 AF XY: 0.00178

Gnomad AFR exome AF: 0.0347

Gnomad AMR exome AF: 0.00139

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00106 AC: 1549 AN: 1461254 Hom.: 36 Cov.: 31 AF XY: 0.000907 AC XY: 659 AN XY: 726912

African (AFR) AF: 0.0376 AC: 1256 AN: 33438

American (AMR) AF: 0.00152 AC: 68 AN: 44652

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39624

South Asian (SAS) AF: 0.000128 AC: 11 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53362

Middle Eastern (MID) AF: 0.00278 AC: 16 AN: 5762

European-Non Finnish (NFE) AF: 0.0000351 AC: 39 AN: 1111680

Other (OTH) AF: 0.00263 AC: 159 AN: 60374

GnomAD4 genome AF: 0.00974 AC: 1483 AN: 152316 Hom.: 21 Cov.: 32 AF XY: 0.00948 AC XY: 706 AN XY: 74494

African (AFR) AF: 0.0340 AC: 1415 AN: 41562

American (AMR) AF: 0.00261 AC: 40 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10632

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 68016

Other (OTH) AF: 0.00665 AC: 14 AN: 2106

Alfa AF: 0.00662 Hom.: 14

Bravo AF: 0.0109

ESP6500AA AF: 0.0325 AC: 143

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00320 AC: 388

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.055
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.032
DANN	Benign	0.26
DEOGEN2	Benign	0.0088	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.27	T
MetaRNN	Benign	0.0025	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-0.020	N
PhyloP100		-0.56
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.25	N
REVEL	Benign	0.022
Sift	Benign	0.38	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.055
MVP		0.040
MPC		0.025
ClinPred		0.00048	T
GERP RS		-3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.017
gMVP		0.13
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs113844295; hg19: chr4-107249319;