chr9-127868305-G-C

Variant names:

• chr9-127868305-G-C
• rs569997176
• NM_000476.3:c.516+16C>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS1

The NM_000476.3(AK1):​c.516+16C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000647 in 1,562,324 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 Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00043 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00067 (0 hom.)
• Consequence: AK1 NM_000476.3 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.98
• Publications: 0 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 9-127868305-G-C is Benign according to our data. Variant chr9-127868305-G-C is described in ClinVar as Likely_benign. ClinVar VariationId is 3603713.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000427 (65/152222) while in subpopulation NFE AF = 0.000764 (52/68028). AF 95% confidence interval is 0.000599. There are 0 homozygotes in GnomAd4. There are 30 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+16C>G		intron	N/A	NP_000467.1	P00568
	AK1	NM_001318122.2		c.564+16C>G		intron	N/A	NP_001305051.1	Q5T9B7
	AK1	NM_001318121.1		c.516+16C>G		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+16C>G		intron	N/A	ENSP00000494600.1	P00568
	ENSG00000257524	ENST00000646171.1		n.*549+16C>G		intron	N/A	ENSP00000495484.1	A0A2R8YFX0
	AK1	ENST00000223836.10	TSL:3	c.564+16C>G		intron	N/A	ENSP00000223836.10	Q5T9B7

Frequencies

GnomAD3 genomes AF: 0.000427 AC: 65 AN: 152222 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000764

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.000278 AC: 48 AN: 172778 AF XY: 0.000305

Gnomad AFR exome AF: 0.000192

Gnomad AMR exome AF: 0.000193

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000772

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000557

Gnomad OTH exome AF: 0.000210

GnomAD4 exome AF: 0.000671 AC: 946 AN: 1410102 Hom.: 0 Cov.: 31 AF XY: 0.000647 AC XY: 451 AN XY: 696984

African (AFR) AF: 0.0000310 AC: 1 AN: 32250

American (AMR) AF: 0.000434 AC: 16 AN: 36902

Ashkenazi Jewish (ASJ) AF: 0.0000394 AC: 1 AN: 25390

East Asian (EAS) AF: 0.0000809 AC: 3 AN: 37102

South Asian (SAS) AF: 0.00 AC: 0 AN: 80868

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4414

European-Non Finnish (NFE) AF: 0.000815 AC: 885 AN: 1085394

Other (OTH) AF: 0.000685 AC: 40 AN: 58384

GnomAD4 genome AF: 0.000427 AC: 65 AN: 152222 Hom.: 0 Cov.: 33 AF XY: 0.000403 AC XY: 30 AN XY: 74376

African (AFR) AF: 0.000217 AC: 9 AN: 41462

American (AMR) AF: 0.0000654 AC: 1 AN: 15282

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000764 AC: 52 AN: 68028

Other (OTH) AF: 0.00143 AC: 3 AN: 2092

Alfa AF: 0.000470 Hom.: 0

Bravo AF: 0.000366

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	5.6
DANN	Benign	0.30
PhyloP100		2.0

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: rs569997176; hg19: chr9-130630584;