7-6009379-G-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_006303.4(AIMP2):c.16G>C(p.Val6Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000821 in 1,611,826 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00084 (3 hom.)
• Consequence: AIMP2 NM_006303.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 6.14

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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008596867).
• BP6: Variant 7-6009379-G-C is Benign according to our data. Variant chr7-6009379-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 444713.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000838 (1223/1459496) while in subpopulation MID AF= 0.00603 (25/4148). AF 95% confidence interval is 0.00419. There are 3 homozygotes in gnomad4_exome. There are 636 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AIMP2	NM_006303.4	c.16G>C	p.Val6Leu	missense_variant	1/4	ENST00000223029.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AIMP2	ENST00000223029.8	c.16G>C	p.Val6Leu	missense_variant	1/4	1	NM_006303.4	P1
AIMP2	ENST00000400479.6	c.-251+1G>C		splice_donor_variant		5
AIMP2	ENST00000395236.2	c.16G>C	p.Val6Leu	missense_variant	1/3	2
AIMP2	ENST00000415999.1	c.16G>C	p.Val6Leu	missense_variant, NMD_transcript_variant	1/3	3

Frequencies

GnomAD3 genomes AF: 0.000657 AC: 100 AN: 152212 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000882

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.00109 AC: 273 AN: 250554 Hom.: 2 AF XY: 0.00110 AC XY: 149 AN XY: 135682

Gnomad AFR exome AF: 0.000372

Gnomad AMR exome AF: 0.000752

Gnomad ASJ exome AF: 0.00786

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000948

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00108

Gnomad OTH exome AF: 0.00180

GnomAD4 exome AF: 0.000838 AC: 1223 AN: 1459496 Hom.: 3 Cov.: 33 AF XY: 0.000876 AC XY: 636 AN XY: 726046

Gnomad4 AFR exome AF: 0.000180

Gnomad4 AMR exome AF: 0.000604

Gnomad4 ASJ exome AF: 0.00681

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000986

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000715

Gnomad4 OTH exome AF: 0.00176

GnomAD4 genome AF: 0.000656 AC: 100 AN: 152330 Hom.: 0 Cov.: 32 AF XY: 0.000644 AC XY: 48 AN XY: 74484

Gnomad4 AFR AF: 0.0000962

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00634

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000882

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.00124 Hom.: 1

Bravo AF: 0.000642

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00140 AC: 12

ExAC AF: 0.00102 AC: 124

EpiCase AF: 0.00185

EpiControl AF: 0.00172

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 11, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.34
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.29
Cadd	Uncertain	25
Dann	Uncertain	0.99
DEOGEN2	Benign	0.055	T;.
Eigen	Benign	-0.0074
Eigen_PC	Benign	0.14
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.83	T;T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.0086	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M;M
MutationTaster	Benign	0.99	D;D;N
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	0.44	N;N
REVEL	Benign	0.16
Sift	Benign	0.40	T;T
Sift4G	Benign	0.70	T;T
Polyphen		0.084	B;.
Vest4		0.67
MutPred		0.24		Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);
MVP		0.21
MPC		0.10
ClinPred		0.050	T
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.31
gMVP		0.43

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

LitVar

Other links and lift over

dbSNP: rs139842556; hg19: chr7-6049010;