NM_000476.3:c.*54C>A

Variant names:

• chr9-127867954-G-T
• rs4226
• NM_000476.3:c.*54C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000476.3(AK1):​c.*54C>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.778 in 1,578,842 control chromosomes in the GnomAD database, including 484,622 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.68 (37957 hom., cov: 34)
  • Exomes 𝑓: 0.79 (446665 hom.)
• Consequence: AK1 NM_000476.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.00400
• Publications: 20 publications found

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]

AK1 Gene-Disease associations (from GenCC):

• hemolytic anemia due to adenylate kinase deficiency

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics

ENSG00000257524 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 9-127867954-G-T is Benign according to our data. Variant chr9-127867954-G-T is described in ClinVar as Benign. ClinVar VariationId is 1232991.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.863 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000476.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AK1	NM_000476.3	MANE Select	c.*54C>A		3_prime_UTR	Exon 7 of 7	NP_000467.1	P00568
	AK1	NM_001318122.2		c.*54C>A		3_prime_UTR	Exon 6 of 6	NP_001305051.1	Q5T9B7
	AK1	NM_001318121.1		c.*54C>A		3_prime_UTR	Exon 7 of 7	NP_001305050.1	Q6FGX9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AK1	ENST00000644144.2	MANE Select	c.*54C>A		3_prime_UTR	Exon 7 of 7	ENSP00000494600.1	P00568
	ENSG00000257524	ENST00000646171.1		n.*672C>A		non_coding_transcript_exon	Exon 13 of 13	ENSP00000495484.1	A0A2R8YFX0
	ENSG00000257524	ENST00000646171.1		n.*672C>A		3_prime_UTR	Exon 13 of 13	ENSP00000495484.1	A0A2R8YFX0

Frequencies

GnomAD3 genomes AF: 0.685 AC: 104143 AN: 152030 Hom.: 37960 Cov.: 34

Gnomad AFR AF: 0.418

Gnomad AMI AF: 0.864

Gnomad AMR AF: 0.682

Gnomad ASJ AF: 0.755

Gnomad EAS AF: 0.885

Gnomad SAS AF: 0.741

Gnomad FIN AF: 0.836

Gnomad MID AF: 0.696

Gnomad NFE AF: 0.799

Gnomad OTH AF: 0.697

GnomAD4 exome AF: 0.788 AC: 1124404 AN: 1426694 Hom.: 446665 Cov.: 26 AF XY: 0.788 AC XY: 560774 AN XY: 711878

African (AFR) AF: 0.402 AC: 13150 AN: 32716

American (AMR) AF: 0.706 AC: 31540 AN: 44650

Ashkenazi Jewish (ASJ) AF: 0.752 AC: 19514 AN: 25934

East Asian (EAS) AF: 0.877 AC: 34672 AN: 39518

South Asian (SAS) AF: 0.734 AC: 62736 AN: 85512

European-Finnish (FIN) AF: 0.826 AC: 44109 AN: 53374

Middle Eastern (MID) AF: 0.700 AC: 3974 AN: 5674

European-Non Finnish (NFE) AF: 0.805 AC: 869378 AN: 1080122

Other (OTH) AF: 0.766 AC: 45331 AN: 59194

GnomAD4 genome AF: 0.685 AC: 104159 AN: 152148 Hom.: 37957 Cov.: 34 AF XY: 0.686 AC XY: 50998 AN XY: 74394

African (AFR) AF: 0.418 AC: 17323 AN: 41476

American (AMR) AF: 0.681 AC: 10419 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.755 AC: 2620 AN: 3472

East Asian (EAS) AF: 0.885 AC: 4578 AN: 5174

South Asian (SAS) AF: 0.741 AC: 3575 AN: 4822

European-Finnish (FIN) AF: 0.836 AC: 8857 AN: 10596

Middle Eastern (MID) AF: 0.704 AC: 207 AN: 294

European-Non Finnish (NFE) AF: 0.799 AC: 54317 AN: 67996

Other (OTH) AF: 0.698 AC: 1475 AN: 2114

Alfa AF: 0.708 Hom.: 10602

Bravo AF: 0.664

Asia WGS AF: 0.781 AC: 2717 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.8
DANN	Benign	0.71
PhyloP100		0.0040
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4226; hg19: chr9-130630233; COSMIC: COSV56345209; COSMIC: COSV56345209;