ENST00000341676.9:c.3361A>T

Variant names:

• chr1-16986101-T-A
• rs41273151
• ENST00000341676.9:c.3361A>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000341676.9(ATP13A2):​c.3361A>T​(p.Thr1121Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00533 in 1,555,544 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0041 (6 hom., cov: 31)
  • Exomes 𝑓: 0.0055 (18 hom.)
• Consequence: ATP13A2 ENST00000341676.9 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.390
• Publications: 5 publications found

Genes affected

ATP13A2 (HGNC:30213): (ATPase cation transporting 13A2) This gene encodes a member of the P5 subfamily of ATPases which transports inorganic cations as well as other substrates. Mutations in this gene are associated with Kufor-Rakeb syndrome (KRS), also referred to as Parkinson disease 9. Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Nov 2008]

ATP13A2 Gene-Disease associations (from GenCC):

• Kufor-Rakeb syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Genomics England PanelApp, G2P, ClinGen, Labcorp Genetics (formerly Invitae), Illumina
• autosomal recessive spastic paraplegia type 78

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae)
• parkinsonism due to ATP13A2 deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000226526 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0053931773).
• BP6: Variant 1-16986101-T-A is Benign according to our data. Variant chr1-16986101-T-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 493023.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00405 (590/145580) while in subpopulation NFE AF = 0.00626 (413/66022). AF 95% confidence interval is 0.00576. There are 6 homozygotes in GnomAd4. There are 269 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000341676.9. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP13A2	NM_022089.4	MANE Select	c.*120A>T		3_prime_UTR	Exon 29 of 29	NP_071372.1	Q9NQ11-1
	ATP13A2	NM_001141974.3		c.3361A>T	p.Thr1121Ser	missense	Exon 27 of 27	NP_001135446.1	Q9NQ11-2
	ATP13A2	NM_001141973.3		c.*120A>T		3_prime_UTR	Exon 29 of 29	NP_001135445.1	Q9NQ11-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP13A2	ENST00000341676.9	TSL:1	c.3361A>T	p.Thr1121Ser	missense	Exon 27 of 27	ENSP00000341115.5	Q9NQ11-2
	ATP13A2	ENST00000326735.13	TSL:1 MANE Select	c.*120A>T		3_prime_UTR	Exon 29 of 29	ENSP00000327214.8	Q9NQ11-1
	ATP13A2	ENST00000452699.5	TSL:1	c.*120A>T		3_prime_UTR	Exon 29 of 29	ENSP00000413307.1	Q9NQ11-3

Frequencies

GnomAD3 genomes AF: 0.00406 AC: 590 AN: 145466 Hom.: 6 Cov.: 31

Gnomad AFR AF: 0.00119

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00572

Gnomad ASJ AF: 0.00382

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00219

Gnomad MID AF: 0.00323

Gnomad NFE AF: 0.00625

Gnomad OTH AF: 0.00545

GnomAD2 exomes AF: 0.00350 AC: 615 AN: 175576 AF XY: 0.00323

Gnomad AFR exome AF: 0.00111

Gnomad AMR exome AF: 0.00331

Gnomad ASJ exome AF: 0.00162

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00278

Gnomad NFE exome AF: 0.00579

Gnomad OTH exome AF: 0.00566

GnomAD4 exome AF: 0.00547 AC: 7708 AN: 1409964 Hom.: 18 Cov.: 31 AF XY: 0.00530 AC XY: 3690 AN XY: 696420

African (AFR) AF: 0.00105 AC: 34 AN: 32328

American (AMR) AF: 0.00388 AC: 135 AN: 34756

Ashkenazi Jewish (ASJ) AF: 0.00191 AC: 47 AN: 24624

East Asian (EAS) AF: 0.00 AC: 0 AN: 37362

South Asian (SAS) AF: 0.0000752 AC: 6 AN: 79750

European-Finnish (FIN) AF: 0.00309 AC: 156 AN: 50472

Middle Eastern (MID) AF: 0.00213 AC: 12 AN: 5640

European-Non Finnish (NFE) AF: 0.00648 AC: 7038 AN: 1086596

Other (OTH) AF: 0.00479 AC: 280 AN: 58436

GnomAD4 genome AF: 0.00405 AC: 590 AN: 145580 Hom.: 6 Cov.: 31 AF XY: 0.00380 AC XY: 269 AN XY: 70882

African (AFR) AF: 0.00118 AC: 46 AN: 38848

American (AMR) AF: 0.00571 AC: 84 AN: 14706

Ashkenazi Jewish (ASJ) AF: 0.00382 AC: 13 AN: 3402

East Asian (EAS) AF: 0.00 AC: 0 AN: 4888

South Asian (SAS) AF: 0.00 AC: 0 AN: 4462

European-Finnish (FIN) AF: 0.00219 AC: 22 AN: 10032

Middle Eastern (MID) AF: 0.00350 AC: 1 AN: 286

European-Non Finnish (NFE) AF: 0.00626 AC: 413 AN: 66022

Other (OTH) AF: 0.00539 AC: 11 AN: 2042

Alfa AF: 0.00513 Hom.: 0

Bravo AF: 0.00428

TwinsUK AF: 0.00539 AC: 20

ALSPAC AF: 0.00571 AC: 22

ESP6500AA AF: 0.000723 AC: 1

ESP6500EA AF: 0.00440 AC: 14

ExAC AF: 0.00285 AC: 338

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	Kufor-Rakeb syndrome (2)
-	-	1	ATP13A2-related disorder (1)
-	-	1	Congenital cerebellar hypoplasia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	0.48
DANN	Benign	0.90
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.31	T
MetaRNN	Benign	0.0054	T
MetaSVM	Benign	-0.30	T
PhyloP100		-0.39
PROVEAN	Benign	-0.41	N
REVEL	Benign	0.15
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.67	T
Vest4		0.17
MutPred		0.10		Loss of sheet (P = 0.1158)
MVP		0.42
ClinPred		0.018	T
GERP RS		-0.83
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=93/7	polymorphism

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: rs41273151; hg19: chr1-17312596;