rs143547136

Variant names:

• chr19-41987936-G-A
• rs143547136
• NM_152296.5:c.357C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_152296.5(ATP1A3):​c.357C>T​(p.Asn119Asn) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00223 in 1,613,566 control chromosomes in the GnomAD database, including 16 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0013 (2 hom., cov: 31)
  • Exomes 𝑓: 0.0023 (14 hom.)
• Consequence: ATP1A3 NM_152296.5 splice_region, synonymous
• Scores: Splicing: ADA: 0.0008782
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:18
• Conservation: PhyloP100: -1.52
• Publications: 3 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 19-41987936-G-A is Benign according to our data. Variant chr19-41987936-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 329427.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.52 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0013 (198/152266) while in subpopulation SAS AF = 0.00787 (38/4830). AF 95% confidence interval is 0.00589. There are 2 homozygotes in GnomAd4. There are 93 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.357C>T	p.Asn119Asn	splice_region synonymous	Exon 4 of 23	NP_689509.1	P13637-1
	ATP1A3	NM_001256214.2		c.396C>T	p.Asn132Asn	splice_region synonymous	Exon 4 of 23	NP_001243143.1	P13637-3
	ATP1A3	NM_001256213.2		c.390C>T	p.Asn130Asn	splice_region synonymous	Exon 4 of 23	NP_001243142.1	P13637-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP1A3	ENST00000648268.1	MANE Select	c.357C>T	p.Asn119Asn	splice_region synonymous	Exon 4 of 23	ENSP00000498113.1	P13637-1
	ENSG00000285505	ENST00000644613.1		n.357C>T		splice_region non_coding_transcript_exon	Exon 4 of 25	ENSP00000494711.1	A0A2R8YEY8
	ATP1A3	ENST00000545399.6	TSL:2	c.396C>T	p.Asn132Asn	splice_region synonymous	Exon 4 of 23	ENSP00000444688.1	P13637-3

Frequencies

GnomAD3 genomes AF: 0.00130 AC: 198 AN: 152148 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00786

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00200

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00241 AC: 604 AN: 251120 AF XY: 0.00287

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.000492

Gnomad ASJ exome AF: 0.000198

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.000700

Gnomad NFE exome AF: 0.00225

Gnomad OTH exome AF: 0.00179

GnomAD4 exome AF: 0.00233 AC: 3403 AN: 1461300 Hom.: 14 Cov.: 32 AF XY: 0.00254 AC XY: 1843 AN XY: 726942

African (AFR) AF: 0.000359 AC: 12 AN: 33462

American (AMR) AF: 0.000492 AC: 22 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000727 AC: 19 AN: 26136

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

South Asian (SAS) AF: 0.00922 AC: 795 AN: 86240

European-Finnish (FIN) AF: 0.000752 AC: 40 AN: 53200

Middle Eastern (MID) AF: 0.00128 AC: 7 AN: 5472

European-Non Finnish (NFE) AF: 0.00216 AC: 2398 AN: 1112004

Other (OTH) AF: 0.00179 AC: 108 AN: 60362

GnomAD4 genome AF: 0.00130 AC: 198 AN: 152266 Hom.: 2 Cov.: 31 AF XY: 0.00125 AC XY: 93 AN XY: 74460

African (AFR) AF: 0.000193 AC: 8 AN: 41546

American (AMR) AF: 0.000261 AC: 4 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.000864 AC: 3 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00787 AC: 38 AN: 4830

European-Finnish (FIN) AF: 0.000565 AC: 6 AN: 10616

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

European-Non Finnish (NFE) AF: 0.00200 AC: 136 AN: 68000

Other (OTH) AF: 0.00142 AC: 3 AN: 2110

Alfa AF: 0.00198 Hom.: 1

Bravo AF: 0.00113

Asia WGS AF: 0.00606 AC: 21 AN: 3478

EpiCase AF: 0.00174

EpiControl AF: 0.00196

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)
-	-	1	ATP1A3-related disorder (1)
-	-	1	Cerebellar ataxia-areflexia-pes cavus-optic atrophy-sensorineural hearing loss syndrome (1)
-	-	1	Cerebellar ataxia-areflexia-pes cavus-optic atrophy-sensorineural hearing loss syndrome;C1868681:Dystonia 12;C3553788:Alternating hemiplegia of childhood 2;C5562018:Developmental and epileptic encephalopathy 99 (1)
-	-	1	Developmental and epileptic encephalopathy 99 (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	0.22
DANN	Benign	0.76
PhyloP100		-1.5
Mutation Taster		=68/32	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00088
dbscSNV1_RF	Benign	0.10
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: rs143547136; hg19: chr19-42492088;