rs777096695

Variant names:

• chr7-141611288-G-A
• rs777096695
• NM_018238.4:c.390+1G>A

Your query was ambiguous. Multiple possible variants found:

• chr7-141611288-G-A
• chr7-141611288-G-T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The NM_018238.4(AGK):​c.390+1G>A variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,452,470 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. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: AGK NM_018238.4 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 8.24
• 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: Likely_pathogenic. The variant received 6 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.07328605 fraction of the gene. Cryptic splice site detected, with MaxEntScore 8.7, offset of 35, new splice context is: aagGTgaga. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-141611288-G-A is Pathogenic according to our data. Variant chr7-141611288-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 467793.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGK	NM_018238.4	c.390+1G>A		splice_donor_variant, intron_variant	Intron 6 of 15	ENST00000649286.2	NP_060708.1
AGK	NM_001364948.3	c.390+1G>A		splice_donor_variant, intron_variant	Intron 6 of 14		NP_001351877.1
AGK	XM_011516397.4	c.390+1G>A		splice_donor_variant, intron_variant	Intron 6 of 15		XP_011514699.1
AGK	XM_024446835.2	c.390+1G>A		splice_donor_variant, intron_variant	Intron 6 of 15		XP_024302603.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AGK	ENST00000649286.2	c.390+1G>A		splice_donor_variant, intron_variant	Intron 6 of 15		NM_018238.4	ENSP00000497280.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000415 AC: 1 AN: 240988 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: 0.0000466

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1452470 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 722566

⚠️ 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: 33190

American (AMR) AF: 0.00 AC: 0 AN: 43938

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25956

East Asian (EAS) AF: 0.00 AC: 0 AN: 39518

South Asian (SAS) AF: 0.00 AC: 0 AN: 84684

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53200

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5726

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1106222

Other (OTH) AF: 0.00 AC: 0 AN: 60036

⚠️ 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

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Sengers syndrome Pathogenic:1

Feb 22, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects a donor splice site in intron 6 of the AGK gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant has not been reported in the literature in individuals with an AGK-related disease. In summary, donor and acceptor splice site variants are typically loss-of-function (PMID: 16199547), and loss-of-function variants in AGK are known to be pathogenic (PMID: 22284826). However, without additional functional and/or genetic data, this variant has been classified as Likely Pathogenic. -

Sengers syndrome;C3553494:Cataract 38 Pathogenic:1

Feb 06, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, donor and acceptor splice site variants are typically loss-of-function (PMID: 16199547), and loss-of-function variants in AGK are known to be pathogenic (PMID: 22284826). However, without additional functional and/or genetic data, this variant has been classified as Likely Pathogenic. This variant has not been reported in the literature in individuals with an AGK-related disease. This sequence change affects a donor splice site in intron 6 of the AGK gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	36
DANN	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		8.2
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.91		Position offset: 34
DS_DL_spliceai		1.0		Position offset: -1

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

Other links and lift over

dbSNP: rs777096695; hg19: chr7-141311088;