9-127868428-C-T
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Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP3BS1_Supporting
The NM_000476.3(AK1):c.409G>A(p.Gly137Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000254 in 1,611,710 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 Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000016 ( 0 hom. )
Consequence
AK1
NM_000476.3 missense
NM_000476.3 missense
Scores
5
11
3
Clinical Significance
Conservation
PhyloP100: 7.47
Genes affected
AK1 (HGNC:361): (adenylate kinase 1) This gene encodes an adenylate kinase enzyme involved in energy metabolism and homeostasis of cellular adenine nucleotide ratios in different intracellular compartments. This gene is highly expressed in skeletal muscle, brain and erythrocytes. Certain mutations in this gene resulting in a functionally inadequate enzyme are associated with a rare genetic disorder causing nonspherocytic hemolytic anemia. Alternative splicing of this gene results in multiple transcript variants encoding different isoforms. This gene shares readthrough transcripts with the upstream ST6GALNAC6 gene. [provided by RefSeq, Jan 2022]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.753
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000118 (18/152150) while in subpopulation AFR AF= 0.000386 (16/41420). AF 95% confidence interval is 0.000242. There are 0 homozygotes in gnomad4. There are 6 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
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
AK1 | NM_000476.3 | c.409G>A | p.Gly137Arg | missense_variant | 6/7 | ENST00000644144.2 | NP_000467.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
AK1 | ENST00000644144.2 | c.409G>A | p.Gly137Arg | missense_variant | 6/7 | NM_000476.3 | ENSP00000494600.1 | |||
ENSG00000257524 | ENST00000646171.1 | n.*442G>A | non_coding_transcript_exon_variant | 12/13 | ENSP00000495484.1 | |||||
ENSG00000257524 | ENST00000646171.1 | n.*442G>A | 3_prime_UTR_variant | 12/13 | ENSP00000495484.1 |
Frequencies
GnomAD3 genomes AF: 0.000118 AC: 18AN: 152150Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000366 AC: 9AN: 245868Hom.: 0 AF XY: 0.0000376 AC XY: 5AN XY: 132982
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GnomAD4 exome AF: 0.0000158 AC: 23AN: 1459560Hom.: 0 Cov.: 36 AF XY: 0.0000138 AC XY: 10AN XY: 725794
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GnomAD4 genome AF: 0.000118 AC: 18AN: 152150Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6AN XY: 74330
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 07, 2021 | The c.409G>A (p.G137R) alteration is located in exon 6 (coding exon 5) of the AK1 gene. This alteration results from a G to A substitution at nucleotide position 409, causing the glycine (G) at amino acid position 137 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Hemolytic anemia due to adenylate kinase deficiency Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Dec 12, 2022 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
D;D;D;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
.;.;D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M;M;M;.
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;.;D;D
REVEL
Uncertain
Sift
Benign
T;.;T;D
Sift4G
Benign
T;.;T;T
Polyphen
D;D;D;.
Vest4
MutPred
Gain of solvent accessibility (P = 0.0037);Gain of solvent accessibility (P = 0.0037);Gain of solvent accessibility (P = 0.0037);.;
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
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