chr3-193491389-T-C

Variant names:

• chr3-193491389-T-C
• rs6788448
• NM_032279.4:c.543A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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 (★★).

• Frequency:
  • Genomes: 𝑓 0.44 (14831 hom., cov: 32)
  • Exomes 𝑓: 0.41 (120481 hom.)
• Consequence: ATP13A4 NM_032279.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.414
• Publications: 37 publications found

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]

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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	c.543A>G	p.Ile181Met	missense_variant	Exon 6 of 30	ENST00000342695.9	NP_115655.2
ATP13A4	XM_047449063.1	c.672A>G	p.Ile224Met	missense_variant	Exon 8 of 32		XP_047305019.1
ATP13A4	XM_017007319.2	c.672A>G	p.Ile224Met	missense_variant	Exon 8 of 27		XP_016862808.2
ATP13A4	XR_007095757.1	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	c.543A>G	p.Ile181Met	missense_variant	Exon 6 of 30	1	NM_032279.4	ENSP00000339182.4

Frequencies

GnomAD3 genomes AF: 0.439 AC: 66755 AN: 151896 Hom.: 14813 Cov.: 32

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

GnomAD2 exomes AF: 0.428 AC: 107402 AN: 250688 AF XY: 0.424

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 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.: 30 AF XY: 0.408 AC XY: 291041 AN XY: 712910

African (AFR) AF: 0.514 AC: 16775 AN: 32636

American (AMR) AF: 0.519 AC: 23163 AN: 44662

Ashkenazi Jewish (ASJ) AF: 0.369 AC: 9552 AN: 25918

East Asian (EAS) AF: 0.412 AC: 16247 AN: 39434

South Asian (SAS) AF: 0.447 AC: 38217 AN: 85544

European-Finnish (FIN) AF: 0.347 AC: 18387 AN: 53008

Middle Eastern (MID) AF: 0.418 AC: 2383 AN: 5702

European-Non Finnish (NFE) AF: 0.400 AC: 433729 AN: 1083120

Other (OTH) AF: 0.413 AC: 24508 AN: 59384

GnomAD4 genome AF: 0.440 AC: 66815 AN: 152014 Hom.: 14831 Cov.: 32 AF XY: 0.438 AC XY: 32534 AN XY: 74312

African (AFR) AF: 0.509 AC: 21127 AN: 41478

American (AMR) AF: 0.486 AC: 7426 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.367 AC: 1273 AN: 3472

East Asian (EAS) AF: 0.439 AC: 2270 AN: 5168

South Asian (SAS) AF: 0.459 AC: 2205 AN: 4808

European-Finnish (FIN) AF: 0.349 AC: 3691 AN: 10566

Middle Eastern (MID) AF: 0.455 AC: 133 AN: 292

European-Non Finnish (NFE) AF: 0.404 AC: 27445 AN: 67932

Other (OTH) AF: 0.427 AC: 901 AN: 2110

Alfa AF: 0.417 Hom.: 63291

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

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	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.029	T;T;.
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.73	T;T;T
MetaRNN	Benign	0.00091	T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Uncertain	2.1	.;M;M
PhyloP100		-0.41
PrimateAI	Uncertain	0.57	T
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	T
GERP RS		4.6
Varity_R		0.29
gMVP		0.78
Mutation Taster		=85/15	polymorphism (auto)

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

Other links and lift over

dbSNP: rs6788448; hg19: chr3-193209178; COSMIC: COSV55066065;