9-127868063-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 4P and 3B. PM1 PM2 BP4_Moderate BS1_Supporting

The NM_000476.3(AK1):c.530G>A(p.Gly177Asp) variant causes a missense change. The variant allele was found at a frequency of 0.000379 in 1,614,090 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G177V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00029 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00039 (0 hom.)
• Consequence: AK1 NM_000476.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.61

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 Uncertain_significance. Variant got 1 ACMG points.

• PM1: In a binding_site (size 0) in uniprot entity KAD1_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2518608).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000289 (44/152284) while in subpopulation NFE AF= 0.000441 (30/68026). AF 95% confidence interval is 0.000317. There are 0 homozygotes in gnomad4. There are 20 alleles in male gnomad4 subpopulation. Median coverage is 33. 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	UniProt
AK1	NM_000476.3	c.530G>A	p.Gly177Asp	missense_variant	7/7	ENST00000644144.2
ST6GALNAC4-ST6GALNAC6-AK1	NR_174625.1	n.3849G>A		non_coding_transcript_exon_variant	15/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AK1	ENST00000644144.2	c.530G>A	p.Gly177Asp	missense_variant	7/7		NM_000476.3	P1

Frequencies

GnomAD3 genomes AF: 0.000289 AC: 44 AN: 152166 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000249 AC: 62 AN: 249166 Hom.: 0 AF XY: 0.000289 AC XY: 39 AN XY: 134880

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.000466

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000388 AC: 567 AN: 1461806 Hom.: 0 Cov.: 33 AF XY: 0.000377 AC XY: 274 AN XY: 727210

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000187

Gnomad4 NFE exome AF: 0.000478

Gnomad4 OTH exome AF: 0.000315

GnomAD4 genome AF: 0.000289 AC: 44 AN: 152284 Hom.: 0 Cov.: 33 AF XY: 0.000269 AC XY: 20 AN XY: 74442

Gnomad4 AFR AF: 0.000168

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000442 Hom.: 0

Bravo AF: 0.000249

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000255 AC: 31

EpiCase AF: 0.000545

EpiControl AF: 0.000356

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hemolytic anemia due to adenylate kinase deficiency Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Nov 16, 2023

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Uncertain	-0.060
Cadd	Benign	23
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.63	D;D;D;.
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.91	D
M_CAP	Benign	0.052	D
MetaRNN	Benign	0.25	T;T;T;T
MetaSVM	Uncertain	-0.28	T
MutationAssessor	Uncertain	2.5	M;M;M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-3.5	D;.;D;D
REVEL	Uncertain	0.33
Sift	Benign	0.092	T;.;T;D
Sift4G	Benign	0.45	T;.;T;T
Polyphen		0.80	P;P;P;.
Vest4		0.43
MVP		0.38
MPC		1.0
ClinPred		0.51	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.55
gMVP		0.67

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs201453879; hg19: chr9-130630342;