9-127868521-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS1

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:2

Conservation

PhyloP100: 0.0680

Variant links:

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 links:

ST6GALNAC4-ST6GALNAC6-AK1 (HGNC:):

ST6GALNAC4-ST6GALNAC6-AK1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 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.

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes

AF:

0.00165

AC:

251

AN:

152088

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.00211

AC XY:

202

AN XY:

95948

show subpopulations

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.:

Cov.:

AF XY:

0.00223

AC XY:

1567

AN XY:

701710

show subpopulations

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.:

Cov.:

AF XY:

0.00175

AC XY:

130

AN XY:

74422

show subpopulations

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.:

Bravo

AF:

0.00182

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 04, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.59

Cadd

Benign

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over