rs35902264

chr9-127868353-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000476.3(AK1):c.484G>A(p.Ala162Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00271 in 1,606,966 control chromosomes in the GnomAD database, including 74 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0075 (17 hom., cov: 33)
  • Exomes 𝑓: 0.0022 (57 hom.)
• Consequence: AK1 NM_000476.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.104

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=0.005394697).
• BP6: Variant 9-127868353-C-T is Benign according to our data. Variant chr9-127868353-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 376798.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00751 (1144/152300) while in subpopulation SAS AF= 0.0274 (132/4822). AF 95% confidence interval is 0.0236. There are 17 homozygotes in gnomad4. There are 572 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 17 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AK1	NM_000476.3	c.484G>A	p.Ala162Thr	missense_variant	6/7	ENST00000644144.2
ST6GALNAC4-ST6GALNAC6-AK1	NR_174625.1	n.3803G>A		non_coding_transcript_exon_variant	14/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AK1	ENST00000644144.2	c.484G>A	p.Ala162Thr	missense_variant	6/7		NM_000476.3	P1

Frequencies

GnomAD3 genomes AF: 0.00752 AC: 1144 AN: 152182 Hom.: 17 Cov.: 33

Gnomad AFR AF: 0.0230

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00270

Gnomad SAS AF: 0.0274

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00479

GnomAD3 exomes AF: 0.00506 AC: 1207 AN: 238538 Hom.: 14 AF XY: 0.00564 AC XY: 727 AN XY: 128954

Gnomad AFR exome AF: 0.0233

Gnomad AMR exome AF: 0.000780

Gnomad ASJ exome AF: 0.000102

Gnomad EAS exome AF: 0.00300

Gnomad SAS exome AF: 0.0255

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000838

Gnomad OTH exome AF: 0.00321

GnomAD4 exome AF: 0.00220 AC: 3207 AN: 1454666 Hom.: 57 Cov.: 32 AF XY: 0.00276 AC XY: 1997 AN XY: 722880

Gnomad4 AFR exome AF: 0.0227

Gnomad4 AMR exome AF: 0.000915

Gnomad4 ASJ exome AF: 0.0000385

Gnomad4 EAS exome AF: 0.00144

Gnomad4 SAS exome AF: 0.0247

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000343

Gnomad4 OTH exome AF: 0.00329

GnomAD4 genome AF: 0.00751 AC: 1144 AN: 152300 Hom.: 17 Cov.: 33 AF XY: 0.00768 AC XY: 572 AN XY: 74474

Gnomad4 AFR AF: 0.0229

Gnomad4 AMR AF: 0.00163

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00270

Gnomad4 SAS AF: 0.0274

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00474

Alfa AF: 0.00120 Hom.: 1

Bravo AF: 0.00742

ESP6500AA AF: 0.0202 AC: 89

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00569 AC: 691

Asia WGS AF: 0.0120 AC: 40 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Sep 09, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 10, 2017	- -

Hemolytic anemia due to adenylate kinase deficiency Benign:1

Likely benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Sep 11, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.39
Cadd	Benign	2.4
Dann	Benign	0.92
DEOGEN2	Benign	0.32	T;T;T;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.085	N
MetaRNN	Benign	0.0054	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L;L;L;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.54	N;.;N;N
REVEL	Benign	0.11
Sift	Benign	0.51	T;.;T;T
Sift4G	Benign	0.57	T;.;T;T
Polyphen		0.017	B;B;B;.
Vest4		0.079
MVP		0.58
MPC		0.29
ClinPred		0.0020	T
GERP RS		-2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.12
gMVP		0.36

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

Other links and lift over

dbSNP: rs35902264; hg19: chr9-130630632;