rs8192462

chr9-127868470-C-G

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 5.74

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]

ST6GALNAC4-ST6GALNAC6-AK1 (HGNC:):

ACMG classification

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 1 benign (89%) 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/exons	MANE	UniProt
AK1	NM_000476.3	c.367G>C	p.Glu123Gln	missense_variant	6/7	ENST00000644144.2
ST6GALNAC4-ST6GALNAC6-AK1	NR_174625.1	n.3686G>C		non_coding_transcript_exon_variant	14/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AK1	ENST00000644144.2	c.367G>C	p.Glu123Gln	missense_variant	6/7		NM_000476.3	P1

Frequencies

GnomAD3 genomes AF: 0.0273 AC: 4153 AN: 152134 Hom.: 91 Cov.: 32

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

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.: 36 AF XY: 0.0408 AC XY: 29404 AN XY: 720990

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.: 92 Cov.: 32 AF XY: 0.0277 AC XY: 2065 AN XY: 74450

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: 24

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:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2021	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 28, 2016

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

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 30, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.21
Cadd	Uncertain	24
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	D
MetaRNN	Benign	0.0022	T;T;T;T
MetaSVM	Benign	-0.55	T
MutationAssessor	Uncertain	2.1	M;M;M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.44	T
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	T
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

Other links and lift over

dbSNP: rs8192462; hg19: chr9-130630749;