rs8192462

Variant names:

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

The NM_000476.3(AK1):c.367G>C(p.Glu123Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0379 in 1,603,830 control chromosomes in the GnomAD database, including 1,477 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.027 ( 92 hom., cov: 32)

Exomes 𝑓: 0.039 ( 1385 hom. )

Consequence

AK1
NM_000476.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 5.74

Variant links:

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]

AK1 links:

ENSG00000257524 (HGNC:):

ENSG00000257524 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

PM1

In a chain Adenylate kinase isoenzyme 1 (size 193) in uniprot entity KAD1_HUMAN there are 8 pathogenic changes around while only 2 benign (80%) in NM_000476.3

BP4

Computational evidence support a benign effect (MetaRNN=0.0022380948).

BP6

Variant 9-127868470-C-G is Benign according to our data. Variant chr9-127868470-C-G is described in ClinVar as [Benign]. Clinvar id is 402354.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0895 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AK1	NM_000476.3 link	c.367G>C	p.Glu123Gln	missense_variant	Exon 6 of 7	ENST00000644144.2	NP_000467.1	P00568Q6FGX9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AK1	ENST00000644144.2 link	c.367G>C	p.Glu123Gln	missense_variant	Exon 6 of 7	NM_000476.3	ENSP00000494600.1	P00568
ENSG00000257524	ENST00000646171.1 link	n.*400G>C		non_coding_transcript_exon_variant	Exon 12 of 13		ENSP00000495484.1	A0A2R8YFX0
ENSG00000257524	ENST00000646171.1 link	n.*400G>C		3_prime_UTR_variant	Exon 12 of 13		ENSP00000495484.1	A0A2R8YFX0

Frequencies

GnomAD3 genomes

AF:

0.0273

AC:

4153

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00649

Gnomad AMI

AF:

0.0143

Gnomad AMR

AF:

0.0196

Gnomad ASJ

AF:

0.0730

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.0960

Gnomad FIN

AF:

0.0291

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.0363

Gnomad OTH

AF:

0.0334

GnomAD3 exomes

AF:

0.0383

AC:

8841

AN:

231078

Hom.:

298

AF XY:

0.0416

AC XY:

5190

AN XY:

124716

show subpopulations

Gnomad AFR exome

AF:

0.00627

Gnomad AMR exome

AF:

0.0133

Gnomad ASJ exome

AF:

0.0751

Gnomad EAS exome

AF:

0.000173

Gnomad SAS exome

AF:

0.102

Gnomad FIN exome

AF:

0.0319

Gnomad NFE exome

AF:

0.0372

Gnomad OTH exome

AF:

0.0418

GnomAD4 exome

AF:

0.0390

AC:

56553

AN:

1451578

Hom.:

1385

Cov.:

AF XY:

0.0408

AC XY:

29404

AN XY:

720990

show subpopulations

Gnomad4 AFR exome

AF:

0.00570

Gnomad4 AMR exome

AF:

0.0146

Gnomad4 ASJ exome

AF:

0.0695

Gnomad4 EAS exome

AF:

0.000178

Gnomad4 SAS exome

AF:

0.0999

Gnomad4 FIN exome

AF:

0.0329

Gnomad4 NFE exome

AF:

0.0372

Gnomad4 OTH exome

AF:

0.0402

GnomAD4 genome

AF:

0.0273

AC:

4158

AN:

152252

Hom.:

Cov.:

AF XY:

0.0277

AC XY:

2065

AN XY:

74450

show subpopulations

Gnomad4 AFR

AF:

0.00650

Gnomad4 AMR

AF:

0.0195

Gnomad4 ASJ

AF:

0.0730

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.0967

Gnomad4 FIN

AF:

0.0291

Gnomad4 NFE

AF:

0.0363

Gnomad4 OTH

AF:

0.0331

Alfa

AF:

0.0372

Hom.:

106

Bravo

AF:

0.0246

ESP6500AA

AF:

0.00545

AC:

ESP6500EA

AF:

0.0367

AC:

316

ExAC

AF:

0.0369

AC:

4482

Asia WGS

AF:

0.0400

AC:

137

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Jan 16, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 09, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified

Benign:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Hemolytic anemia due to adenylate kinase deficiency

Benign:1

Nov 01, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.21

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.56

D;D;D;.

Eigen

Benign

0.15

Eigen_PC

Uncertain

0.25

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.96

.;.;D;D

MetaRNN

Benign

0.0022

T;T;T;T

MetaSVM

Benign

-0.55

MutationAssessor

Uncertain

2.1

M;M;M;.

PrimateAI

Benign

0.44

PROVEAN

Benign

-1.9

N;.;N;N

REVEL

Benign

0.21

Sift

Benign

0.081

T;.;T;T

Sift4G

Uncertain

0.059

T;.;T;T

Polyphen

0.15

B;B;B;.

Vest4

0.26

MPC

0.35

ClinPred

0.012

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.67

gMVP

0.69

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over