chr13-24680753-G-A

Variant names:

• chr13-24680753-G-A
• rs762356809
• NM_001676.7:c.9+1G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 4P and 4B. PVS1_Strong BS2

The NM_001676.7(ATP12A):​c.9+1G>A variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000893 in 1,499,786 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency:
  • Genomes: 𝑓 0.00081 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00090 (2 hom.)
• Consequence: ATP12A NM_001676.7 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 2.39
• Publications: 1 publications found

Genes affected

ATP12A (HGNC:13816): (ATPase H+/K+ transporting non-gastric alpha2 subunit) The protein encoded by this gene belongs to the family of P-type cation transport ATPases. This gene encodes a catalytic subunit of the ouabain-sensitive H+/K+ -ATPase that catalyzes the hydrolysis of ATP coupled with the exchange of H(+) and K(+) ions across the plasma membrane. It is also responsible for potassium absorption in various tissues. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jun 2010]

ENSG00000303666 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.11057692 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP12A	NM_001676.7	c.9+1G>A		splice_donor_variant, intron_variant	Intron 1 of 22	ENST00000381946.5	NP_001667.4
ATP12A	NM_001185085.2	c.9+1G>A		splice_donor_variant, intron_variant	Intron 1 of 22		NP_001172014.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP12A	ENST00000381946.5	c.9+1G>A		splice_donor_variant, intron_variant	Intron 1 of 22	1	NM_001676.7	ENSP00000371372.3
ATP12A	ENST00000218548.10	c.9+1G>A		splice_donor_variant, intron_variant	Intron 1 of 22	1		ENSP00000218548.6
ENSG00000303666	ENST00000796402.1	n.72+3747C>T		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes AF: 0.000808 AC: 123 AN: 152224 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000753

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00146

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000688 AC: 65 AN: 94542 AF XY: 0.000695

Gnomad AFR exome AF: 0.00144

Gnomad AMR exome AF: 0.000201

Gnomad ASJ exome AF: 0.00207

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000957

Gnomad NFE exome AF: 0.00105

Gnomad OTH exome AF: 0.00139

GnomAD4 exome AF: 0.000903 AC: 1217 AN: 1347446 Hom.: 2 Cov.: 30 AF XY: 0.000894 AC XY: 594 AN XY: 664316

African (AFR) AF: 0.000146 AC: 4 AN: 27386

American (AMR) AF: 0.000221 AC: 7 AN: 31658

Ashkenazi Jewish (ASJ) AF: 0.00281 AC: 67 AN: 23822

East Asian (EAS) AF: 0.00 AC: 0 AN: 30924

South Asian (SAS) AF: 0.00 AC: 0 AN: 75624

European-Finnish (FIN) AF: 0.00144 AC: 48 AN: 33436

Middle Eastern (MID) AF: 0.000221 AC: 1 AN: 4524

European-Non Finnish (NFE) AF: 0.000984 AC: 1047 AN: 1063864

Other (OTH) AF: 0.000765 AC: 43 AN: 56208

GnomAD4 genome AF: 0.000807 AC: 123 AN: 152340 Hom.: 0 Cov.: 33 AF XY: 0.000671 AC XY: 50 AN XY: 74496

African (AFR) AF: 0.0000240 AC: 1 AN: 41588

American (AMR) AF: 0.000196 AC: 3 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00317 AC: 11 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.000753 AC: 8 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00146 AC: 99 AN: 68026

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.00245 Hom.: 1

Bravo AF: 0.000559

ExAC AF: 0.000536 AC: 9

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

not provided Uncertain:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.039	T
BayesDel_noAF	Pathogenic	0.17
CADD	Pathogenic	32
DANN	Uncertain	0.98
Eigen	Pathogenic	0.82
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Benign	0.71	D
PhyloP100		2.4
GERP RS		3.1
PromoterAI		-0.34	Neutral
Mutation Taster		=71/29	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.98		Position offset: -1

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

Other links and lift over

dbSNP: rs762356809; hg19: chr13-25254891; COSMIC: COSV99517862;