chr9-127868521-G-A

Position:

• chr9-127868521-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000476.3(AK1):​c.325-9C>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00221 in 1,570,652 control chromosomes in the GnomAD database, including 11 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: 32)
  • Exomes 𝑓: 0.0023 (11 hom.)
• Consequence: AK1 NM_000476.3 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0001377
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.0680

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]

ST6GALNAC4-ST6GALNAC6-AK1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 9-127868521-G-A is Benign according to our data. Variant chr9-127868521-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 776766.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-127868521-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00165 (251/152206) while in subpopulation AMR AF= 0.00307 (47/15298). AF 95% confidence interval is 0.00237. There are 0 homozygotes in gnomad4. There are 130 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AK1	NM_000476.3	c.325-9C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000644144.2	NP_000467.1
ST6GALNAC4-ST6GALNAC6-AK1	NR_174625.1	n.3644-9C>T		splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AK1	ENST00000644144.2	c.325-9C>T		splice_polypyrimidine_tract_variant, intron_variant			NM_000476.3	ENSP00000494600	P1

Frequencies

GnomAD3 genomes AF: 0.00165 AC: 251 AN: 152088 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00308

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00237

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00212 AC: 382 AN: 180200 Hom.: 1 AF XY: 0.00211 AC XY: 202 AN XY: 95948

Gnomad AFR exome AF: 0.00101

Gnomad AMR exome AF: 0.00369

Gnomad ASJ exome AF: 0.00146

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000857

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00300

Gnomad OTH exome AF: 0.00287

GnomAD4 exome AF: 0.00227 AC: 3216 AN: 1418446 Hom.: 11 Cov.: 36 AF XY: 0.00223 AC XY: 1567 AN XY: 701710

Gnomad4 AFR exome AF: 0.000738

Gnomad4 AMR exome AF: 0.00302

Gnomad4 ASJ exome AF: 0.00134

Gnomad4 EAS exome AF: 0.0000532

Gnomad4 SAS exome AF: 0.00115

Gnomad4 FIN exome AF: 0.0000994

Gnomad4 NFE exome AF: 0.00256

Gnomad4 OTH exome AF: 0.00228

GnomAD4 genome AF: 0.00165 AC: 251 AN: 152206 Hom.: 0 Cov.: 32 AF XY: 0.00175 AC XY: 130 AN XY: 74422

Gnomad4 AFR AF: 0.000506

Gnomad4 AMR AF: 0.00307

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00207

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.00237

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00115 Hom.: 0

Bravo AF: 0.00182

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 04, 2024	- -

Hemolytic anemia due to adenylate kinase deficiency Benign:1

Likely benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Feb 22, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	11
DANN	Benign	0.85

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00014
dbscSNV1_RF	Benign	0.31
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: rs145431113; hg19: chr9-130630800; COSMIC: COSV56345256; COSMIC: COSV56345256;