1-65218864-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong

The NM_013410.4(AK4):​c.376C>T​(p.Arg126Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000621 in 1,609,820 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 0.000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000062 ( 0 hom. )

Consequence

AK4
NM_013410.4 missense

Scores

11
6
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.52
Variant links:
Genes affected
AK4 (HGNC:363): (adenylate kinase 4) This gene encodes a member of the adenylate kinase family of enzymes. The encoded protein is localized to the mitochondrial matrix. Adenylate kinases regulate the adenine and guanine nucleotide compositions within a cell by catalyzing the reversible transfer of phosphate group among these nucleotides. Five isozymes of adenylate kinase have been identified in vertebrates. Expression of these isozymes is tissue-specific and developmentally regulated. A pseudogene for this gene has been located on chromosome 17. Three transcript variants encoding the same protein have been identified for this gene. Sequence alignment suggests that the gene defined by NM_013410, NM_203464, and NM_001005353 is located on chromosome 1. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM1
In a binding_site (size 0) in uniprot entity KAD4_HUMAN
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.97

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
AK4NM_013410.4 linkuse as main transcriptc.376C>T p.Arg126Cys missense_variant 3/5 ENST00000327299.8 NP_037542.1 P27144

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
AK4ENST00000327299.8 linkuse as main transcriptc.376C>T p.Arg126Cys missense_variant 3/51 NM_013410.4 ENSP00000322175.7 P27144

Frequencies

GnomAD3 genomes
AF:
0.0000657
AC:
10
AN:
152156
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000145
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000588
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000446
AC:
11
AN:
246672
Hom.:
0
AF XY:
0.0000524
AC XY:
7
AN XY:
133664
show subpopulations
Gnomad AFR exome
AF:
0.0000639
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000892
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000617
AC:
90
AN:
1457664
Hom.:
0
Cov.:
30
AF XY:
0.0000593
AC XY:
43
AN XY:
725164
show subpopulations
Gnomad4 AFR exome
AF:
0.0000301
Gnomad4 AMR exome
AF:
0.0000454
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000188
Gnomad4 NFE exome
AF:
0.0000766
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000657
AC:
10
AN:
152156
Hom.:
0
Cov.:
32
AF XY:
0.0000807
AC XY:
6
AN XY:
74320
show subpopulations
Gnomad4 AFR
AF:
0.000145
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000588
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000762
Hom.:
0
Bravo
AF:
0.0000416
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000494
AC:
6

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJan 02, 2024The c.376C>T (p.R126C) alteration is located in exon 4 (coding exon 3) of the AK4 gene. This alteration results from a C to T substitution at nucleotide position 376, causing the arginine (R) at amino acid position 126 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.60
BayesDel_addAF
Pathogenic
0.40
D
BayesDel_noAF
Pathogenic
0.53
CADD
Pathogenic
27
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.82
D;D;D;D
Eigen
Uncertain
0.66
Eigen_PC
Uncertain
0.55
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Benign
0.86
.;D;D;.
M_CAP
Pathogenic
0.64
D
MetaRNN
Pathogenic
0.97
D;D;D;D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Pathogenic
4.5
H;.;H;H
PrimateAI
Uncertain
0.63
T
PROVEAN
Pathogenic
-7.2
D;D;D;D
REVEL
Pathogenic
0.79
Sift
Pathogenic
0.0
D;D;D;D
Sift4G
Uncertain
0.056
T;T;T;T
Polyphen
0.83
P;.;P;P
Vest4
0.95
MVP
0.99
MPC
1.5
ClinPred
0.99
D
GERP RS
4.8
Varity_R
0.92
gMVP
0.96

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs376330094; hg19: chr1-65684547; API