Genetic Variant PANK4:p.Ala547Val (chr1-2512975-G-A) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_018216.4(PANK4):c.1640C>T(p.Ala547Val) variant causes a missense change. The variant allele was found at a frequency of 0.344 in 1,611,998 control chromosomes in the GnomAD database, including 100,597 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A547S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.28 ( 7170 hom., cov: 35)

Exomes 𝑓: 0.35 ( 93427 hom. )

Consequence

PANK4
NM_018216.4 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 4.00

Publications

56 publications found

Variant links:

Genes affected

PANK4 (HGNC:19366): (pantothenate kinase 4 (inactive)) This gene encodes a protein belonging to the pantothenate kinase family. Pantothenate kinase is a key regulatory enzyme in the biosynthesis of coenzyme A (CoA) in bacteria and mammalian cells. It catalyzes the first committed step in the universal biosynthetic pathway leading to CoA and is itself subject to regulation through feedback inhibition by CoA. This family member is most abundant in muscle but is expressed in all tissues. [provided by RefSeq, Jul 2008]

PANK4 Gene-Disease associations (from GenCC):

early-onset posterior polar cataract
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
cataract
Inheritance: AD Classification: LIMITED Submitted by: G2P
cataract 49
Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

PANK4 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009886503).

BP6

Variant 1-2512975-G-A is Benign according to our data. Variant chr1-2512975-G-A is described in ClinVar as [Benign]. Clinvar id is 2585653.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.372 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PANK4	NM_018216.4 link	c.1640C>T	p.Ala547Val	missense_variant	Exon 13 of 19	ENST00000378466.9	NP_060686.3	Q9NVE7
PANK4	XM_047424306.1 link	c.1199C>T	p.Ala400Val	missense_variant	Exon 13 of 19		XP_047280262.1
PANK4	XR_241034.4 link	n.1649C>T		non_coding_transcript_exon_variant	Exon 13 of 17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PANK4	ENST00000378466.9 link	c.1640C>T	p.Ala547Val	missense_variant	Exon 13 of 19	1	NM_018216.4	ENSP00000367727.5		Q9NVE7

Frequencies

GnomAD3 genomes

AF:

0.275

AC:

41906

AN:

152114

Hom.:

7171

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0678

Gnomad AMI

AF:

0.507

Gnomad AMR

AF:

0.290

Gnomad ASJ

AF:

0.377

Gnomad EAS

AF:

0.344

Gnomad SAS

AF:

0.239

Gnomad FIN

AF:

0.346

Gnomad MID

AF:

0.316

Gnomad NFE

AF:

0.376

Gnomad OTH

AF:

0.315

GnomAD2 exomes

AF:

0.315

AC:

78659

AN:

249742

AF XY:

0.322

show subpopulations

Gnomad AFR exome

AF:

0.0627

Gnomad AMR exome

AF:

0.232

Gnomad ASJ exome

AF:

0.375

Gnomad EAS exome

AF:

0.360

Gnomad FIN exome

AF:

0.351

Gnomad NFE exome

AF:

0.375

Gnomad OTH exome

AF:

0.351

GnomAD4 exome

AF:

0.352

AC:

513284

AN:

1459764

Hom.:

93427

Cov.:

AF XY:

0.350

AC XY:

254196

AN XY:

726178

show subpopulations

African (AFR)

AF:

0.0539

AC:

1803

AN:

33460

American (AMR)

AF:

0.241

AC:

10775

AN:

44688

Ashkenazi Jewish (ASJ)

AF:

0.375

AC:

9797

AN:

26094

East Asian (EAS)

AF:

0.380

AC:

15073

AN:

39684

South Asian (SAS)

AF:

0.247

AC:

21336

AN:

86220

European-Finnish (FIN)

AF:

0.353

AC:

18422

AN:

52144

Middle Eastern (MID)

AF:

0.339

AC:

1953

AN:

5766

European-Non Finnish (NFE)

AF:

0.372

AC:

413930

AN:

1111368

Other (OTH)

AF:

0.335

AC:

20195

AN:

60340

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

18166

36331

54497

72662

90828

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.275

AC:

41894

AN:

152234

Hom.:

7170

Cov.:

AF XY:

0.274

AC XY:

20419

AN XY:

74438

show subpopulations

African (AFR)

AF:

0.0676

AC:

2809

AN:

41574

American (AMR)

AF:

0.290

AC:

4435

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.377

AC:

1309

AN:

3470

East Asian (EAS)

AF:

0.344

AC:

1780

AN:

5174

South Asian (SAS)

AF:

0.238

AC:

1147

AN:

4822

European-Finnish (FIN)

AF:

0.346

AC:

3660

AN:

10592

Middle Eastern (MID)

AF:

0.323

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.376

AC:

25541

AN:

67994

Other (OTH)

AF:

0.312

AC:

657

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

1497

2995

4492

5990

7487

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.346

Hom.:

19367

Bravo

AF:

0.264

TwinsUK

AF:

0.357

AC:

1322

ALSPAC

AF:

0.368

AC:

1417

ESP6500AA

AF:

0.0717

AC:

316

ESP6500EA

AF:

0.375

AC:

3222

ExAC

AF:

0.312

AC:

37849

Asia WGS

AF:

0.219

AC:

761

AN:

3478

EpiCase

AF:

0.388

EpiControl

AF:

0.380

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Cataract 49

Benign:1

Apr 11, 2023

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.089

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.46

CADD

Benign

(source)

DANN

Uncertain

1.0

Eigen

Benign

-0.12

Eigen_PC

Benign

-0.13

FATHMM_MKL

Benign

0.65

LIST_S2

Benign

0.66

T;.

MetaRNN

Benign

0.0099

T;T

MetaSVM

Benign

-0.87

PhyloP100

4.0

PrimateAI

Benign

0.31

REVEL

Benign

0.091

Sift4G

Benign

0.11

T;T

Vest4

0.050

MPC

0.66

ClinPred

0.028

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=98/2

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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chr1-2512975-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over