rs191645384

Variant names:

• chr19-41988144-G-C
• rs191645384
• NM_152296.5:c.154-5C>G

Variant summary

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

The NM_152296.5(ATP1A3):​c.154-5C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0035 in 1,614,112 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0023 (2 hom., cov: 31)
  • Exomes 𝑓: 0.0036 (31 hom.)
• Consequence: ATP1A3 NM_152296.5 splice_region, intron
• Scores: Splicing: ADA: 0.01178
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:17
• Conservation: PhyloP100: 0.449
• Publications: 1 publications found

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]

ATP1A3 Gene-Disease associations (from GenCC):

• alternating hemiplegia of childhood 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp, G2P
• ATP1A3-associated neurological disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: Illumina, ClinGen
• cerebellar ataxia-areflexia-pes cavus-optic atrophy-sensorineural hearing loss syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, Genomics England PanelApp
• developmental and epileptic encephalopathy 99

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• dystonia 12

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, Genomics England PanelApp
• encephalopathy, acute, infection-induced

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• alternating hemiplegia of childhood

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• complex neurodevelopmental disorder

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ENSG00000285505 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 19-41988144-G-C is Benign according to our data. Variant chr19-41988144-G-C is described in ClinVar as Benign. ClinVar VariationId is 281502.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00225 (343/152240) while in subpopulation SAS AF = 0.0137 (66/4832). AF 95% confidence interval is 0.011. There are 2 homozygotes in GnomAd4. There are 172 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152296.5. 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
	ATP1A3	NM_152296.5	MANE Select	c.154-5C>G		splice_region intron	N/A	NP_689509.1	P13637-1
	ATP1A3	NM_001256214.2		c.193-5C>G		splice_region intron	N/A	NP_001243143.1	P13637-3
	ATP1A3	NM_001256213.2		c.187-5C>G		splice_region intron	N/A	NP_001243142.1	P13637-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP1A3	ENST00000648268.1	MANE Select	c.154-5C>G		splice_region intron	N/A	ENSP00000498113.1	P13637-1
	ENSG00000285505	ENST00000644613.1		n.154-5C>G		splice_region intron	N/A	ENSP00000494711.1	A0A2R8YEY8
	ATP1A3	ENST00000545399.6	TSL:2	c.193-5C>G		splice_region intron	N/A	ENSP00000444688.1	P13637-3

Frequencies

GnomAD3 genomes AF: 0.00224 AC: 340 AN: 152122 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.000604

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0130

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00315

Gnomad OTH AF: 0.00479

GnomAD2 exomes AF: 0.00345 AC: 866 AN: 250822 AF XY: 0.00423

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.000954

Gnomad ASJ exome AF: 0.00119

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00286

Gnomad OTH exome AF: 0.00310

GnomAD4 exome AF: 0.00363 AC: 5301 AN: 1461872 Hom.: 31 Cov.: 33 AF XY: 0.00401 AC XY: 2919 AN XY: 727236

African (AFR) AF: 0.000568 AC: 19 AN: 33480

American (AMR) AF: 0.00105 AC: 47 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00119 AC: 31 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.0161 AC: 1393 AN: 86256

European-Finnish (FIN) AF: 0.000243 AC: 13 AN: 53414

Middle Eastern (MID) AF: 0.00486 AC: 28 AN: 5764

European-Non Finnish (NFE) AF: 0.00320 AC: 3563 AN: 1112004

Other (OTH) AF: 0.00339 AC: 205 AN: 60396

GnomAD4 genome AF: 0.00225 AC: 343 AN: 152240 Hom.: 2 Cov.: 31 AF XY: 0.00231 AC XY: 172 AN XY: 74442

African (AFR) AF: 0.000602 AC: 25 AN: 41524

American (AMR) AF: 0.00111 AC: 17 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5176

South Asian (SAS) AF: 0.0137 AC: 66 AN: 4832

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00315 AC: 214 AN: 68006

Other (OTH) AF: 0.00474 AC: 10 AN: 2108

Alfa AF: 0.00277 Hom.: 1

Bravo AF: 0.00186

Asia WGS AF: 0.00606 AC: 21 AN: 3478

EpiCase AF: 0.00338

EpiControl AF: 0.00320

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not provided (8)
-	-	3	Dystonia 12 (3)
-	-	2	Alternating hemiplegia of childhood 2 (2)
-	-	2	not specified (2)
-	-	1	Cerebellar ataxia-areflexia-pes cavus-optic atrophy-sensorineural hearing loss syndrome (1)
-	-	1	Developmental and epileptic encephalopathy 99 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	13
DANN	Benign	0.51
PhyloP100		0.45
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.012
dbscSNV1_RF	Benign	0.13
SpliceAI score (max)		0.10		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: rs191645384; hg19: chr19-42492296;