dbSNP rs6788448: ATP13A4:p.Ile181Met (chr3-193491389-T-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_032279.4(ATP13A4):c.543A>G(p.Ile181Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.411 in 1,581,422 control chromosomes in the GnomAD database, including 135,312 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.44 ( 14831 hom., cov: 32)

Exomes 𝑓: 0.41 ( 120481 hom. )

Consequence

ATP13A4
NM_032279.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.414

Variant links:

Genes affected

ATP13A4 (HGNC:25422): (ATPase 13A4) Predicted to enable ATPase-coupled cation transmembrane transporter activity. Predicted to be involved in cellular calcium ion homeostasis. Predicted to be located in endoplasmic reticulum membrane and endosome membrane. [provided by Alliance of Genome Resources, Apr 2022]

ATP13A4 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=9.139776E-4).

BP6

Variant 3-193491389-T-C is Benign according to our data. Variant chr3-193491389-T-C is described in ClinVar as [Benign]. Clinvar id is 1229084.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.504 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP13A4	NM_032279.4 link	c.543A>G	p.Ile181Met	missense_variant	Exon 6 of 30	ENST00000342695.9	NP_115655.2	Q4VNC1-1B3KU47
ATP13A4	XM_047449063.1 link	c.672A>G	p.Ile224Met	missense_variant	Exon 8 of 32		XP_047305019.1
ATP13A4	XM_017007319.2 link	c.672A>G	p.Ile224Met	missense_variant	Exon 8 of 27		XP_016862808.2
ATP13A4	XR_007095757.1 link	n.936A>G		non_coding_transcript_exon_variant	Exon 8 of 26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP13A4	ENST00000342695.9 link	c.543A>G	p.Ile181Met	missense_variant	Exon 6 of 30	1	NM_032279.4	ENSP00000339182.4		Q4VNC1-1

Frequencies

GnomAD3 genomes

AF:

0.439

AC:

66755

AN:

151896

Hom.:

14813

Cov.:

show subpopulations

Gnomad AFR

AF:

0.509

Gnomad AMI

AF:

0.377

Gnomad AMR

AF:

0.486

Gnomad ASJ

AF:

0.367

Gnomad EAS

AF:

0.439

Gnomad SAS

AF:

0.458

Gnomad FIN

AF:

0.349

Gnomad MID

AF:

0.455

Gnomad NFE

AF:

0.404

Gnomad OTH

AF:

0.431

GnomAD3 exomes

AF:

0.428

AC:

107402

AN:

250688

Hom.:

23521

AF XY:

0.424

AC XY:

57527

AN XY:

135556

show subpopulations

Gnomad AFR exome

AF:

0.512

Gnomad AMR exome

AF:

0.522

Gnomad ASJ exome

AF:

0.366

Gnomad EAS exome

AF:

0.443

Gnomad SAS exome

AF:

0.449

Gnomad FIN exome

AF:

0.349

Gnomad NFE exome

AF:

0.400

Gnomad OTH exome

AF:

0.431

GnomAD4 exome

AF:

0.408

AC:

582961

AN:

1429408

Hom.:

120481

Cov.:

AF XY:

0.408

AC XY:

291041

AN XY:

712910

show subpopulations

Gnomad4 AFR exome

AF:

0.514

Gnomad4 AMR exome

AF:

0.519

Gnomad4 ASJ exome

AF:

0.369

Gnomad4 EAS exome

AF:

0.412

Gnomad4 SAS exome

AF:

0.447

Gnomad4 FIN exome

AF:

0.347

Gnomad4 NFE exome

AF:

0.400

Gnomad4 OTH exome

AF:

0.413

GnomAD4 genome

AF:

0.440

AC:

66815

AN:

152014

Hom.:

14831

Cov.:

AF XY:

0.438

AC XY:

32534

AN XY:

74312

show subpopulations

Gnomad4 AFR

AF:

0.509

Gnomad4 AMR

AF:

0.486

Gnomad4 ASJ

AF:

0.367

Gnomad4 EAS

AF:

0.439

Gnomad4 SAS

AF:

0.459

Gnomad4 FIN

AF:

0.349

Gnomad4 NFE

AF:

0.404

Gnomad4 OTH

AF:

0.427

Alfa

AF:

0.412

Hom.:

33774

Bravo

AF:

0.452

TwinsUK

AF:

0.413

AC:

1532

ALSPAC

AF:

0.405

AC:

1562

ESP6500AA

AF:

0.515

AC:

2270

ESP6500EA

AF:

0.404

AC:

3476

ExAC

AF:

0.427

AC:

51820

Asia WGS

AF:

0.459

AC:

1596

AN:

3474

EpiCase

AF:

0.409

EpiControl

AF:

0.405

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Dec 12, 2018

GeneDx

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

0.21

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.31

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.029

T;T;.

Eigen

Uncertain

0.39

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Benign

0.54

LIST_S2

Benign

0.73

T;T;T

MetaRNN

Benign

0.00091

T;T;T

MetaSVM

Benign

-0.94

MutationAssessor

Uncertain

2.1

.;M;M

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-1.6

N;N;N

REVEL

Uncertain

0.41

Sift

Benign

0.15

T;T;T

Sift4G

Benign

0.11

T;T;T

Polyphen

1.0

.;D;.

Vest4

0.099

MPC

0.55

ClinPred

0.038

GERP RS

4.6

Varity_R

0.29

gMVP

0.78

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