rs771945804

Variant names:

• chr7-141636963-C-A
• rs771945804
• NM_018238.4:c.672C>A

Your query was ambiguous. Multiple possible variants found:

• chr7-141636963-C-A
• chr7-141636963-C-G
• chr7-141636963-C-T

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_018238.4(AGK):​c.672C>A​(p.Tyr224*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000891 in 1,459,650 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: AGK NM_018238.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 1.59
• Publications: 2 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: Pathogenic. The variant received 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 7-141636963-C-A is Pathogenic according to our data. Variant chr7-141636963-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 871496.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.672C>A	p.Tyr224*	stop_gained	Exon 11 of 16	NP_060708.1	Q53H12-1
	AGK	NM_001364948.3		c.672C>A	p.Tyr224*	stop_gained	Exon 11 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.672C>A	p.Tyr224*	stop_gained	Exon 11 of 16	ENSP00000497280.1	Q53H12-1
	AGK	ENST00000912229.1		c.768C>A	p.Tyr256*	stop_gained	Exon 12 of 17	ENSP00000582288.1
	AGK	ENST00000909108.1		c.696C>A	p.Tyr232*	stop_gained	Exon 10 of 15	ENSP00000579167.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000239 AC: 6 AN: 250778 AF XY: 0.0000295

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000441

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000891 AC: 13 AN: 1459650 Hom.: 0 Cov.: 29 AF XY: 0.0000124 AC XY: 9 AN XY: 726196

African (AFR) AF: 0.00 AC: 0 AN: 33384

American (AMR) AF: 0.0000224 AC: 1 AN: 44642

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26072

East Asian (EAS) AF: 0.00 AC: 0 AN: 39614

South Asian (SAS) AF: 0.00 AC: 0 AN: 86070

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53326

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5564

European-Non Finnish (NFE) AF: 0.0000108 AC: 12 AN: 1110702

Other (OTH) AF: 0.00 AC: 0 AN: 60276

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000407 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000247 AC: 3

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	not provided (2)
1	-	-	Sengers syndrome (1)
1	-	-	Sengers syndrome;C3553494:Cataract 38 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	36
DANN	Uncertain	1.0
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.83	D
PhyloP100		1.6
Vest4		0.96
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs771945804; hg19: chr7-141336763;