NM_000476.3:c.516+11C>T

Variant names:

• chr9-127868310-G-A
• rs115263629
• NM_000476.3:c.516+11C>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS1

The NM_000476.3(AK1):​c.516+11C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000308 in 1,566,542 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0016 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00017 (1 hom.)
• Consequence: AK1 NM_000476.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.45
• Publications: 1 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet

ENSG00000257524 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 9-127868310-G-A is Benign according to our data. Variant chr9-127868310-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 1679428.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00158 (240/152346) while in subpopulation AFR AF = 0.00536 (223/41582). AF 95% confidence interval is 0.00479. There are 0 homozygotes in GnomAd4. There are 104 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

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.516+11C>T		intron	N/A	NP_000467.1	P00568
	AK1	NM_001318122.2		c.564+11C>T		intron	N/A	NP_001305051.1	Q5T9B7
	AK1	NM_001318121.1		c.516+11C>T		intron	N/A	NP_001305050.1	Q6FGX9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AK1	ENST00000644144.2	MANE Select	c.516+11C>T		intron	N/A	ENSP00000494600.1	P00568
	ENSG00000257524	ENST00000646171.1		n.*549+11C>T		intron	N/A	ENSP00000495484.1	A0A2R8YFX0
	AK1	ENST00000223836.10	TSL:3	c.564+11C>T		intron	N/A	ENSP00000223836.10	Q5T9B7

Frequencies

GnomAD3 genomes AF: 0.00158 AC: 240 AN: 152228 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00538

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000413

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.000407 AC: 73 AN: 179490 AF XY: 0.000292

Gnomad AFR exome AF: 0.00478

Gnomad AMR exome AF: 0.000602

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000542

Gnomad OTH exome AF: 0.000205

GnomAD4 exome AF: 0.000171 AC: 242 AN: 1414196 Hom.: 1 Cov.: 31 AF XY: 0.000152 AC XY: 106 AN XY: 699450

African (AFR) AF: 0.00521 AC: 169 AN: 32428

American (AMR) AF: 0.000454 AC: 17 AN: 37460

Ashkenazi Jewish (ASJ) AF: 0.0000786 AC: 2 AN: 25440

East Asian (EAS) AF: 0.00 AC: 0 AN: 37516

South Asian (SAS) AF: 0.0000246 AC: 2 AN: 81268

European-Finnish (FIN) AF: 0.0000201 AC: 1 AN: 49682

Middle Eastern (MID) AF: 0.000221 AC: 1 AN: 4516

European-Non Finnish (NFE) AF: 0.0000175 AC: 19 AN: 1087362

Other (OTH) AF: 0.000530 AC: 31 AN: 58524

GnomAD4 genome AF: 0.00158 AC: 240 AN: 152346 Hom.: 0 Cov.: 33 AF XY: 0.00140 AC XY: 104 AN XY: 74498

African (AFR) AF: 0.00536 AC: 223 AN: 41582

American (AMR) AF: 0.000523 AC: 8 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68016

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.0000443 Hom.: 7

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Hemolytic anemia due to adenylate kinase deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.98
DANN	Benign	0.85
PhyloP100		-1.5
Mutation Taster		=100/0	polymorphism

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: rs115263629; hg19: chr9-130630589;