7-141614171-C-A

Variant names:

• chr7-141614171-C-A
• rs144706178
• NM_018238.4:c.416C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_018238.4(AGK):​c.416C>A​(p.Thr139Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000195 in 1,537,864 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T139R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (1 hom.)
• Consequence: AGK NM_018238.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.40
• 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: Labcorp Genetics (formerly Invitae), G2P, Orphanet
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07265186).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGK	NM_018238.4	c.416C>A	p.Thr139Lys	missense_variant	Exon 7 of 16	ENST00000649286.2	NP_060708.1
AGK	NM_001364948.3	c.416C>A	p.Thr139Lys	missense_variant	Exon 7 of 15		NP_001351877.1
AGK	XM_011516397.4	c.416C>A	p.Thr139Lys	missense_variant	Exon 7 of 16		XP_011514699.1
AGK	XM_024446835.2	c.416C>A	p.Thr139Lys	missense_variant	Exon 7 of 16		XP_024302603.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AGK	ENST00000649286.2	c.416C>A	p.Thr139Lys	missense_variant	Exon 7 of 16		NM_018238.4	ENSP00000497280.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152128 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000144 AC: 2 AN: 1385618 Hom.: 1 Cov.: 25 AF XY: 0.00 AC XY: 0 AN XY: 690996

African (AFR) AF: 0.00 AC: 0 AN: 29832

American (AMR) AF: 0.00 AC: 0 AN: 37440

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25110

East Asian (EAS) AF: 0.00 AC: 0 AN: 36310

South Asian (SAS) AF: 0.0000257 AC: 2 AN: 77890

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52666

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5496

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1063458

Other (OTH) AF: 0.00 AC: 0 AN: 57416

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152246 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74442

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

African (AFR) AF: 0.00 AC: 0 AN: 41570

American (AMR) AF: 0.00 AC: 0 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10588

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67990

Other (OTH) AF: 0.00 AC: 0 AN: 2110

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	18
DANN	Benign	0.76
DEOGEN2	Benign	0.037	T;T;T;.;T;.;.;T;T;.
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.29
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.93	.;D;D;D;.;D;D;.;D;D
M_CAP	Benign	0.0043	T
MetaRNN	Benign	0.073	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-0.34	N;.;.;.;N;.;.;N;N;.
PhyloP100		1.4
PrimateAI	Benign	0.38	T
PROVEAN	Benign	0.43	N;.;N;.;.;.;.;.;.;.
REVEL	Benign	0.034
Sift	Benign	0.84	T;.;T;.;.;.;.;.;.;.
Sift4G	Benign	0.89	T;T;T;.;.;.;.;.;.;.
Polyphen		0.0	B;.;.;.;B;.;.;B;B;.
Vest4		0.27
MutPred		0.56		Gain of ubiquitination at T139 (P = 0.0238);.;.;.;Gain of ubiquitination at T139 (P = 0.0238);.;.;Gain of ubiquitination at T139 (P = 0.0238);Gain of ubiquitination at T139 (P = 0.0238);Gain of ubiquitination at T139 (P = 0.0238);
MVP		0.12
MPC		0.25
ClinPred		0.21	T
GERP RS		1.6
Varity_R		0.12
gMVP		0.32
Mutation Taster		=89/11	polymorphism

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

Other links and lift over

dbSNP: rs144706178; hg19: chr7-141313971;