7-6009437-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Moderate PP5_Moderate

The NM_006303.4(AIMP2):c.74A>G(p.Tyr25Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,458,852 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: AIMP2 NM_006303.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.33

Genes affected

AIMP2 (HGNC:20609): (aminoacyl tRNA synthetase complex interacting multifunctional protein 2) The protein encoded by this gene is part of the aminoacyl-tRNA synthetase complex, which contains nine different aminoacyl-tRNA synthetases and three non-enzymatic factors. The encoded protein is one of the non-enzymatic factors and is required for assembly and stability of the complex. [provided by RefSeq, May 2016]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.865
• PP5: Variant 7-6009437-A-G is Pathogenic according to our data. Variant chr7-6009437-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 982311.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AIMP2	NM_006303.4	c.74A>G	p.Tyr25Cys	missense_variant	1/4	ENST00000223029.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AIMP2	ENST00000223029.8	c.74A>G	p.Tyr25Cys	missense_variant	1/4	1	NM_006303.4	P1
AIMP2	ENST00000395236.2	c.74A>G	p.Tyr25Cys	missense_variant	1/3	2
AIMP2	ENST00000400479.6	c.-251+59A>G		intron_variant		5
AIMP2	ENST00000415999.1	c.74A>G	p.Tyr25Cys	missense_variant, NMD_transcript_variant	1/3	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1458852 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 725726

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Leukodystrophy, hypomyelinating, 17 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Department of Medical Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences

-

Analysis of the exome sequencing data showed a novel homozygous sequence variant in AIMP2 gene. This variant is predicted as Disease Causing by MutationTaster. This variant is not found in ExAC and 1000G databases. Sanger sequencing confirmed the variation in the proband and similarly affected female sibling. Parents are heterozygous for the same variation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.27
Cadd	Pathogenic	28
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.65	D;.
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.87	D;D
MetaSVM	Uncertain	0.11	D
MutationAssessor	Uncertain	2.8	M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-7.5	D;D
REVEL	Pathogenic	0.73
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;.
Vest4		0.95
MutPred		0.58		Loss of phosphorylation at Y25 (P = 0.0243);Loss of phosphorylation at Y25 (P = 0.0243);
MVP		0.75
MPC		0.26
ClinPred		1.0	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.95
gMVP		0.82

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-6049068;