9-127868461-T-C

Position:

• chr9-127868461-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000476.3(AK1):​c.376A>G​(p.Thr126Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000275 in 1,455,142 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: AK1 NM_000476.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.07

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]

ENSG00000257524 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33547115).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AK1	NM_000476.3	c.376A>G	p.Thr126Ala	missense_variant	6/7	ENST00000644144.2	NP_000467.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AK1	ENST00000644144.2	c.376A>G	p.Thr126Ala	missense_variant	6/7		NM_000476.3	ENSP00000494600.1
ENSG00000257524	ENST00000646171.1	n.*409A>G		non_coding_transcript_exon_variant	12/13			ENSP00000495484.1
ENSG00000257524	ENST00000646171.1	n.*409A>G		3_prime_UTR_variant	12/13			ENSP00000495484.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000275 AC: 4 AN: 1455142 Hom.: 0 Cov.: 36 AF XY: 0.00000277 AC XY: 2 AN XY: 723108

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: 0.00000361

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 07, 2024

The c.376A>G (p.T126A) alteration is located in exon 6 (coding exon 5) of the AK1 gene. This alteration results from a A to G substitution at nucleotide position 376, causing the threonine (T) at amino acid position 126 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.055	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	23
DANN	Benign	0.84
DEOGEN2	Uncertain	0.52	D;D;D;.
Eigen	Benign	0.18
Eigen_PC	Benign	0.22
FATHMM_MKL	Benign	0.74	D
LIST_S2	Uncertain	0.89	.;.;D;D
M_CAP	Benign	0.053	D
MetaRNN	Benign	0.34	T;T;T;T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	1.7	L;L;L;.
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-2.5	D;.;D;D
REVEL	Benign	0.13
Sift	Benign	0.17	T;.;T;T
Sift4G	Benign	0.45	T;.;T;T
Polyphen		0.029	B;B;B;.
Vest4		0.14
MutPred		0.44		Loss of phosphorylation at T126 (P = 0.0521);Loss of phosphorylation at T126 (P = 0.0521);Loss of phosphorylation at T126 (P = 0.0521);.;
MVP		0.63
MPC		0.30
ClinPred		0.72	D
GERP RS		3.9
Varity_R		0.44
gMVP		0.51

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: rs1399110826; hg19: chr9-130630740;