7-141555499-C-A

Variant names:

• chr7-141555499-C-A
• rs1057524817
• NM_018238.4:c.33C>A

Variant summary

Our verdict is Uncertain significance. The variant received 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
• Publications: 0 publications found

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]

AGK Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Sengers syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P
• total early-onset cataract

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• cataract 38

  Inheritance: AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018238.4. 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
	AGK	NM_018238.4	MANE Select	c.33C>A	p.His11Gln	missense	Exon 2 of 16	NP_060708.1	Q53H12-1
	AGK	NM_001364948.3		c.33C>A	p.His11Gln	missense	Exon 2 of 15	NP_001351877.1	A0A3B3ISZ0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGK	ENST00000649286.2	MANE Select	c.33C>A	p.His11Gln	missense	Exon 2 of 16	ENSP00000497280.1	Q53H12-1
	AGK	ENST00000492693.5	TSL:1	c.33C>A	p.His11Gln	missense	Exon 1 of 3	ENSP00000418789.1	Q53H12-2
	AGK	ENST00000649914.1		c.-194C>A		5_prime_UTR_premature_start_codon_gain	Exon 2 of 16	ENSP00000497848.1	A0A3B3ITD0

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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.0000224 AC: 1 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86218

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111950

Other (OTH) AF: 0.00 AC: 0 AN: 60388

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.035	N
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.057	D
MetaRNN	Benign	0.33	T
MetaSVM	Benign	-0.61	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		-1.3
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-3.1	D
REVEL	Uncertain	0.35
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.0090	D
Polyphen		0.41	B
Vest4		0.71
MutPred		0.57		Gain of catalytic residue at H11 (P = 0.0424)
MVP		0.25
MPC		0.37
ClinPred		0.95	D
GERP RS		-11
PromoterAI		-0.035	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.13
gMVP		0.64
Mutation Taster		=61/39	polymorphism

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

Other links and lift over

dbSNP: rs1057524817; hg19: chr7-141255299;