NM_018238.4:c.1131+5G>A

Variant names:

• chr7-141651614-G-A
• rs542547163
• NM_018238.4:c.1131+5G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP3 PP5

The NM_018238.4(AGK):​c.1131+5G>A variant causes a splice region, intron change. The variant allele was found at a frequency of 0.00000547 in 1,461,648 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: AGK NM_018238.4 splice_region, intron
• Scores: Splicing: ADA: 0.9995
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 6.17
• Publications: 3 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 2 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 7-141651614-G-A is Pathogenic according to our data. Variant chr7-141651614-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 30831.Status of the report is no_assertion_criteria_provided, 0 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGK	NM_018238.4	MANE Select	c.1131+5G>A		splice_region intron	N/A	NP_060708.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGK	ENST00000649286.2	MANE Select	c.1131+5G>A		splice_region intron	N/A	ENSP00000497280.1
	AGK	ENST00000649014.1		n.*411G>A		non_coding_transcript_exon	Exon 14 of 14	ENSP00000497984.1
	AGK	ENST00000649365.1		n.*1144G>A		non_coding_transcript_exon	Exon 16 of 16	ENSP00000496835.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461648 Hom.: 0 Cov.: 30 AF XY: 0.00000550 AC XY: 4 AN XY: 727162

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000720 AC: 8 AN: 1111784

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000312 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Sengers syndrome Pathogenic:1

Feb 10, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.27
CADD	Benign	23
DANN	Benign	0.95
PhyloP100		6.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=9/91	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.86		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.86		Position offset: -5

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

Other links and lift over

dbSNP: rs542547163; hg19: chr7-141351414;