7-141555521-C-T
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Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2
The NM_018238.4(AGK):c.55C>T(p.Leu19Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000188 in 1,614,140 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000092 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00020 ( 3 hom. )
Consequence
AGK
NM_018238.4 missense
NM_018238.4 missense
Scores
1
18
Clinical Significance
Conservation
PhyloP100: 0.0630
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]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -9 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.0261814).
BS1
Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0000919 (14/152332) while in subpopulation SAS AF= 0.00124 (6/4824). AF 95% confidence interval is 0.000541. There are 0 homozygotes in gnomad4. There are 10 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
High Homozygotes in GnomAdExome4 at 3 AR gene
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| AGK | NM_018238.4 | c.55C>T | p.Leu19Phe | missense_variant | 2/16 | ENST00000649286.2 | NP_060708.1 | |
| AGK | NM_001364948.3 | c.55C>T | p.Leu19Phe | missense_variant | 2/15 | NP_001351877.1 | ||
| AGK | XM_011516397.4 | c.55C>T | p.Leu19Phe | missense_variant | 2/16 | XP_011514699.1 | ||
| AGK | XM_024446835.2 | c.55C>T | p.Leu19Phe | missense_variant | 2/16 | XP_024302603.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| AGK | ENST00000649286.2 | c.55C>T | p.Leu19Phe | missense_variant | 2/16 | NM_018238.4 | ENSP00000497280.1 |
Frequencies
GnomAD3 genomes 0.0000920 AC: 14AN: 152214Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000267 AC: 67AN: 251394Hom.: 0 AF XY: 0.000361 AC XY: 49AN XY: 135870
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GnomAD4 exome AF: 0.000198 AC: 290AN: 1461808Hom.: 3 Cov.: 30 AF XY: 0.000256 AC XY: 186AN XY: 727216
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GnomAD4 genome 0.0000919 AC: 14AN: 152332Hom.: 0 Cov.: 32 AF XY: 0.000134 AC XY: 10AN XY: 74488
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:4Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Sengers syndrome;C3553494:Cataract 38 Uncertain:2
| Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 29, 2022 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jul 29, 2022 | This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 19 of the AGK protein (p.Leu19Phe). This variant is present in population databases (rs367844999, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with AGK-related conditions. ClinVar contains an entry for this variant (Variation ID: 909780). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Sengers syndrome Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Cataract 38 Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Inborn genetic diseases Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 15, 2022 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
T;T;T;T;T;.;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Benign
.;T;.;.;T;T;T
M_CAP
Benign
T
MetaRNN
Benign
T;T;T;T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
N;.;N;N;N;.;N
PrimateAI
Benign
T
PROVEAN
Benign
N;.;.;.;.;.;N
REVEL
Benign
Sift
Benign
T;.;.;.;.;.;T
Sift4G
Benign
T;T;.;.;.;.;T
Polyphen
B;.;B;B;B;.;.
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at