dbSNP rs868431923: AGK:c.975+1G>A (chr7-141641909-G-A) – ACMG Classification: Pathogenic (10 pts)

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1PM2

The NM_018238.4(AGK):c.975+1G>A variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.000000704 in 1,420,022 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

AGK
NM_018238.4 splice_donor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.02

Publications

0 publications found

Variant links:

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)

AGK links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
AGK	NM_018238.4 link	c.975+1G>A	splice_donor_variant, intron_variant	Intron 13 of 15	ENST00000649286.2	NP_060708.1	Q53H12-1A4D1U5
AGK	NM_001364948.3 link	c.975+1G>A	splice_donor_variant, intron_variant	Intron 13 of 14		NP_001351877.1
AGK	XM_011516397.4 link	c.975+1G>A	splice_donor_variant, intron_variant	Intron 13 of 15		XP_011514699.1	Q53H12-1A4D1U5
AGK	XM_024446835.2 link	c.975+1G>A	splice_donor_variant, intron_variant	Intron 13 of 15		XP_024302603.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AGK	ENST00000649286.2 link	c.975+1G>A		splice_donor_variant, intron_variant	Intron 13 of 15		NM_018238.4	ENSP00000497280.1		Q53H12-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

186166

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

7.04e-7

AC:

AN:

1420022

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

701826

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32962

American (AMR)

AF:

0.00

AC:

AN:

38120

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25372

East Asian (EAS)

AF:

0.00

AC:

AN:

38378

South Asian (SAS)

AF:

0.00

AC:

AN:

80650

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5718

European-Non Finnish (NFE)

AF:

9.18e-7

AC:

AN:

1089272

Other (OTH)

AF:

0.00

AC:

AN:

58946

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000238

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.62

BayesDel_noAF

Pathogenic

0.18

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Uncertain

0.90

PhyloP100

6.0

GERP RS

4.5

Mutation Taster

=3/97

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.93

Splicevardb

3.0

SpliceAI score (max)

0.98

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.98

Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over