9-127868353-C-T

Position:

chr9-127868353-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000476.3(AK1):c.484G>A(p.Ala162Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00271 in 1,606,966 control chromosomes in the GnomAD database, including 74 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0075 ( 17 hom., cov: 33)

Exomes 𝑓: 0.0022 ( 57 hom. )

Consequence

AK1
NM_000476.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.104

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005394697).

BP6

Variant 9-127868353-C-T is Benign according to our data. Variant chr9-127868353-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 376798.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00751 (1144/152300) while in subpopulation SAS AF= 0.0274 (132/4822). AF 95% confidence interval is 0.0236. There are 17 homozygotes in gnomad4. There are 572 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 17 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AK1	NM_000476.3 linkuse as main transcript	c.484G>A	p.Ala162Thr	missense_variant	6/7	ENST00000644144.2	NP_000467.1
ST6GALNAC4-ST6GALNAC6-AK1	NR_174625.1 linkuse as main transcript	n.3803G>A		non_coding_transcript_exon_variant	14/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AK1	ENST00000644144.2 linkuse as main transcript	c.484G>A	p.Ala162Thr	missense_variant	6/7		NM_000476.3	ENSP00000494600	P1

Frequencies

GnomAD3 genomes

AF:

0.00752

AC:

1144

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0230

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00164

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00270

Gnomad SAS

AF:

0.0274

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.00479

GnomAD3 exomes

AF:

0.00506

AC:

1207

AN:

238538

Hom.:

AF XY:

0.00564

AC XY:

727

AN XY:

128954

show subpopulations

Gnomad AFR exome

AF:

0.0233

Gnomad AMR exome

AF:

0.000780

Gnomad ASJ exome

AF:

0.000102

Gnomad EAS exome

AF:

0.00300

Gnomad SAS exome

AF:

0.0255

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000838

Gnomad OTH exome

AF:

0.00321

GnomAD4 exome

AF:

0.00220

AC:

3207

AN:

1454666

Hom.:

Cov.:

AF XY:

0.00276

AC XY:

1997

AN XY:

722880

show subpopulations

Gnomad4 AFR exome

AF:

0.0227

Gnomad4 AMR exome

AF:

0.000915

Gnomad4 ASJ exome

AF:

0.0000385

Gnomad4 EAS exome

AF:

0.00144

Gnomad4 SAS exome

AF:

0.0247

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000343

Gnomad4 OTH exome

AF:

0.00329

GnomAD4 genome

AF:

0.00751

AC:

1144

AN:

152300

Hom.:

Cov.:

AF XY:

0.00768

AC XY:

572

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.0229

Gnomad4 AMR

AF:

0.00163

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00270

Gnomad4 SAS

AF:

0.0274

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000147

Gnomad4 OTH

AF:

0.00474

Alfa

AF:

0.00120

Hom.:

Bravo

AF:

0.00742

ESP6500AA

AF:

0.0202

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.00569

AC:

691

Asia WGS

AF:

0.0120

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 09, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 10, 2017	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

Sep 11, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.39

CADD

Benign

2.4

DANN

Benign

0.92

DEOGEN2

Benign

0.32

T;T;T;.

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.085

LIST_S2

Benign

0.75

.;.;T;T

MetaRNN

Benign

0.0054

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.1

L;L;L;.

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.54

N;.;N;N

REVEL

Benign

0.11

Sift

Benign

0.51

T;.;T;T

Sift4G

Benign

0.57

T;.;T;T

Polyphen

0.017

B;B;B;.

Vest4

0.079

MVP

0.58

MPC

0.29

ClinPred

0.0020

GERP RS

-2.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.12

gMVP

0.36

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

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