19-41966622-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_152296.5(ATP1A3):c.*315G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0011 in 1,473,200 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00068 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0011 (2 hom.)
• Consequence: ATP1A3 NM_152296.5 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.875

Genes affected

ATP1A3 (HGNC:801): (ATPase Na+/K+ transporting subunit alpha 3) The protein encoded by this gene belongs to the family of P-type cation transport ATPases, and to the subfamily of Na+/K+ -ATPases. Na+/K+ -ATPase is an integral membrane protein responsible for establishing and maintaining the electrochemical gradients of Na and K ions across the plasma membrane. These gradients are essential for osmoregulation, for sodium-coupled transport of a variety of organic and inorganic molecules, and for electrical excitability of nerve and muscle. This enzyme is composed of two subunits, a large catalytic subunit (alpha) and a smaller glycoprotein subunit (beta). The catalytic subunit of Na+/K+ -ATPase is encoded by multiple genes. This gene encodes an alpha 3 subunit. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2012]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 19-41966622-C-T is Benign according to our data. Variant chr19-41966622-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 329395.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 = 0.000677 (103/152098) while in subpopulation NFE AF= 0.00132 (90/68024). AF 95% confidence interval is 0.0011. There are 0 homozygotes in gnomad4. There are 37 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd at 103 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP1A3	NM_152296.5	c.*315G>A		3_prime_UTR_variant	23/23	ENST00000648268.1
ATP1A3	NM_001256213.2	c.*315G>A		3_prime_UTR_variant	23/23
ATP1A3	NM_001256214.2	c.*315G>A		3_prime_UTR_variant	23/23
ATP1A3	XM_047438862.1	c.*315G>A		3_prime_UTR_variant	23/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP1A3	ENST00000648268.1	c.*315G>A		3_prime_UTR_variant	23/23		NM_152296.5

Frequencies

GnomAD3 genomes AF: 0.000677 AC: 103 AN: 152098 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000944

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00132

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000486 AC: 74 AN: 152378 Hom.: 0 AF XY: 0.000416 AC XY: 34 AN XY: 81736

Gnomad AFR exome AF: 0.000292

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00121

Gnomad OTH exome AF: 0.000456

GnomAD4 exome AF: 0.00114 AC: 1511 AN: 1321102 Hom.: 2 Cov.: 32 AF XY: 0.00114 AC XY: 744 AN XY: 649814

Gnomad4 AFR exome AF: 0.000268

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000250

Gnomad4 NFE exome AF: 0.00144

Gnomad4 OTH exome AF: 0.000374

GnomAD4 genome AF: 0.000677 AC: 103 AN: 152098 Hom.: 0 Cov.: 31 AF XY: 0.000498 AC XY: 37 AN XY: 74310

Gnomad4 AFR AF: 0.000290

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000944

Gnomad4 NFE AF: 0.00132

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000803 Hom.: 0

Bravo AF: 0.000756

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Alternating hemiplegia of childhood 2 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -

Dystonia 12 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2023	ATP1A3: BS1 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 23, 2020	- -

Developmental and epileptic encephalopathy 99 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

Cerebellar ataxia-areflexia-pes cavus-optic atrophy-sensorineural hearing loss syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
Cadd	Benign	17
Dann	Uncertain	0.99

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

Other links and lift over

dbSNP: rs571857150; hg19: chr19-42470774; COSMIC: COSV57484879;