rs1376867262

chr7-141601206-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_018238.4(AGK):c.223A>G(p.Lys75Glu) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000755 in 1,457,326 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: AGK NM_018238.4 missense, splice_region
• Scores: Splicing: ADA: 0.8634
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.49

Genes affected

AGK (HGNC:21869): (acylglycerol kinase) The protein encoded by this gene is a mitochondrial membrane protein involved in lipid and glycerolipid metabolism. The encoded protein is a lipid kinase that catalyzes the formation of phosphatidic and lysophosphatidic acids. Defects in this gene have been associated with mitochondrial DNA depletion syndrome 10. [provided by RefSeq, Feb 2012]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AGK	NM_018238.4	c.223A>G	p.Lys75Glu	missense_variant, splice_region_variant	5/16	ENST00000649286.2
AGK	NM_001364948.3	c.223A>G	p.Lys75Glu	missense_variant, splice_region_variant	5/15
AGK	XM_011516397.4	c.223A>G	p.Lys75Glu	missense_variant, splice_region_variant	5/16
AGK	XM_024446835.2	c.223A>G	p.Lys75Glu	missense_variant, splice_region_variant	5/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AGK	ENST00000649286.2	c.223A>G	p.Lys75Glu	missense_variant, splice_region_variant	5/16		NM_018238.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000755 AC: 11 AN: 1457326 Hom.: 0 Cov.: 29 AF XY: 0.00000828 AC XY: 6 AN XY: 725022

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000811

Gnomad4 OTH exome AF: 0.0000332

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

AGK-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Dec 18, 2017

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.34
BayesDel_addAF	Uncertain	0.034	T
BayesDel_noAF	Benign	-0.19
Cadd	Pathogenic	31
Dann	Uncertain	1.0
DEOGEN2	Benign	0.20	T;T;T;.;T;T;.
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.018	T
MetaRNN	Uncertain	0.54	D;D;D;D;D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L;.;L;.;L;L;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-2.5	D;D;.;.;.;.;.
REVEL	Benign	0.18
Sift	Benign	0.12	T;T;.;.;.;.;.
Sift4G	Benign	0.14	T;T;.;.;.;.;.
Polyphen		0.90	P;.;P;.;P;P;.
Vest4		0.80
MutPred		0.58		Loss of MoRF binding (P = 0.0265);.;Loss of MoRF binding (P = 0.0265);.;Loss of MoRF binding (P = 0.0265);Loss of MoRF binding (P = 0.0265);Loss of MoRF binding (P = 0.0265);
MVP		0.28
MPC		0.89
ClinPred		0.96	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.79
gMVP		0.75

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.86
dbscSNV1_RF	Benign	0.69
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

Publications

LitVar

Other links and lift over

dbSNP: rs1376867262; hg19: chr7-141301006;