chr9-127868094-G-A

Variant names:

• chr9-127868094-G-A
• rs7031929
• NM_000476.3:c.517-18C>T

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.517-18C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00294 in 1,613,658 control chromosomes in the GnomAD database, including 108 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (49 hom., cov: 33)
  • Exomes 𝑓: 0.0016 (59 hom.)
• Consequence: AK1 NM_000476.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -3.23
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 9-127868094-G-A is Benign according to our data. Variant chr9-127868094-G-A is described in ClinVar as Benign. ClinVar VariationId is 1330793.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0526 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.517-18C>T		intron	N/A	NP_000467.1	P00568
	AK1	NM_001318122.2		c.565-18C>T		intron	N/A	NP_001305051.1	Q5T9B7
	AK1	NM_001318121.1		c.517-18C>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.517-18C>T		intron	N/A	ENSP00000494600.1	P00568
	ENSG00000257524	ENST00000646171.1		n.*550-18C>T		intron	N/A	ENSP00000495484.1	A0A2R8YFX0
	AK1	ENST00000954057.1		c.523C>T	p.Arg175Trp	missense	Exon 7 of 7	ENSP00000624116.1

Frequencies

GnomAD3 genomes AF: 0.0156 AC: 2372 AN: 152154 Hom.: 48 Cov.: 33

Gnomad AFR AF: 0.0544

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00464

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.0139

GnomAD2 exomes AF: 0.00410 AC: 1019 AN: 248668 AF XY: 0.00284

Gnomad AFR exome AF: 0.0564

Gnomad AMR exome AF: 0.00214

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000153

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.00162 AC: 2373 AN: 1461386 Hom.: 59 Cov.: 33 AF XY: 0.00137 AC XY: 996 AN XY: 727042

African (AFR) AF: 0.0575 AC: 1925 AN: 33460

American (AMR) AF: 0.00282 AC: 126 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26130

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39694

South Asian (SAS) AF: 0.000104 AC: 9 AN: 86238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00209 AC: 12 AN: 5752

European-Non Finnish (NFE) AF: 0.000104 AC: 116 AN: 1111608

Other (OTH) AF: 0.00301 AC: 182 AN: 60374

GnomAD4 genome AF: 0.0156 AC: 2378 AN: 152272 Hom.: 49 Cov.: 33 AF XY: 0.0149 AC XY: 1106 AN XY: 74454

African (AFR) AF: 0.0545 AC: 2263 AN: 41558

American (AMR) AF: 0.00457 AC: 70 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 68014

Other (OTH) AF: 0.0137 AC: 29 AN: 2114

Alfa AF: 0.00758 Hom.: 10

Bravo AF: 0.0175

Asia WGS AF: 0.00404 AC: 14 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: 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	-0.84
CADD	Benign	0.010
DANN	Benign	0.71
PhyloP100		-3.2
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: rs7031929; hg19: chr9-130630373;