7-141555499-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_018238.4(AGK):c.33C>A(p.His11Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,724 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: AGK NM_018238.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.27

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32808393).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AGK	NM_018238.4	c.33C>A	p.His11Gln	missense_variant	2/16	ENST00000649286.2
AGK	NM_001364948.3	c.33C>A	p.His11Gln	missense_variant	2/15
AGK	XM_011516397.4	c.33C>A	p.His11Gln	missense_variant	2/16
AGK	XM_024446835.2	c.33C>A	p.His11Gln	missense_variant	2/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AGK	ENST00000649286.2	c.33C>A	p.His11Gln	missense_variant	2/16		NM_018238.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461724 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727162

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jan 23, 2017

The H11Q variant in the AGK gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. This variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The H11Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Based on currently available evidence, we interpret H11Q as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
Cadd	Benign	7.3
Dann	Benign	0.93
DEOGEN2	Benign	0.28	T;T;T;T;T;.;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.035	N
M_CAP	Benign	0.057	D
MetaRNN	Benign	0.33	T;T;T;T;T;T;T
MetaSVM	Benign	-0.61	T
MutationAssessor	Uncertain	2.2	M;.;M;M;M;.;M
MutationTaster	Benign	0.82	D;D;D;N
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-3.1	D;.;.;.;.;.;D
REVEL	Uncertain	0.35
Sift	Uncertain	0.0070	D;.;.;.;.;.;D
Sift4G	Uncertain	0.0090	D;D;.;.;.;.;D
Polyphen		0.41	B;.;B;B;B;.;.
Vest4		0.71
MutPred		0.57		Gain of catalytic residue at H11 (P = 0.0424);Gain of catalytic residue at H11 (P = 0.0424);Gain of catalytic residue at H11 (P = 0.0424);Gain of catalytic residue at H11 (P = 0.0424);Gain of catalytic residue at H11 (P = 0.0424);Gain of catalytic residue at H11 (P = 0.0424);Gain of catalytic residue at H11 (P = 0.0424);
MVP		0.25
MPC		0.37
ClinPred		0.95	D
GERP RS		-11
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.13
gMVP		0.64

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1057524817; hg19: chr7-141255299;