9-127868455-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_000476.3(AK1):c.382C>T(p.Arg128Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000343 in 1,456,106 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 Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: AK1 NM_000476.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.989

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 Likely_pathogenic. Variant got 9 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
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.983
• PP5: Variant 9-127868455-G-A is Pathogenic according to our data. Variant chr9-127868455-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 18263.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AK1	NM_000476.3	c.382C>T	p.Arg128Trp	missense_variant	6/7	ENST00000644144.2
ST6GALNAC4-ST6GALNAC6-AK1	NR_174625.1	n.3701C>T		non_coding_transcript_exon_variant	14/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AK1	ENST00000644144.2	c.382C>T	p.Arg128Trp	missense_variant	6/7		NM_000476.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000343 AC: 5 AN: 1456106 Hom.: 0 Cov.: 36 AF XY: 0.00000276 AC XY: 2 AN XY: 723734

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000451

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Hemolytic anemia due to adenylate kinase deficiency Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 15, 1989

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.33
Cadd	Uncertain	24
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.94	D;D;D;.
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.85	D
M_CAP	Pathogenic	0.30	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Pathogenic	5.0	H;H;H;.
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-8.0	D;.;D;D
REVEL	Pathogenic	0.85
Sift	Pathogenic	0.0	D;.;D;D
Sift4G	Pathogenic	0.0	D;.;D;D
Polyphen		1.0	D;D;D;.
Vest4		0.93
MutPred		0.95		Loss of disorder (P = 7e-04);Loss of disorder (P = 7e-04);Loss of disorder (P = 7e-04);.;
MVP		0.96
MPC		1.0
ClinPred		1.0	D
GERP RS		1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.97
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

Other links and lift over

dbSNP: rs104894101; hg19: chr9-130630734;