19-41981616-C-T

Variant names:

• chr19-41981616-C-T
• rs34578730
• NM_152296.5:c.1323G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_152296.5(ATP1A3):​c.1323G>A​(p.Ala441Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00975 in 1,614,192 control chromosomes in the GnomAD database, including 102 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A441A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0062 (8 hom., cov: 31)
  • Exomes 𝑓: 0.010 (94 hom.)
• Consequence: ATP1A3 NM_152296.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:12
• Conservation: PhyloP100: 1.18
• Publications: 2 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: Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• ATP1A3-associated neurological disorder

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

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

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

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.19).
• BP6: Variant 19-41981616-C-T is Benign according to our data. Variant chr19-41981616-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 157924.
• BP7: Synonymous conserved (PhyloP=1.17 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0062 (944/152302) while in subpopulation NFE AF = 0.0107 (727/68036). AF 95% confidence interval is 0.01. There are 8 homozygotes in GnomAd4. There are 451 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 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.1323G>A	p.Ala441Ala	synonymous	Exon 11 of 23	NP_689509.1	P13637-1
	ATP1A3	NM_001256214.2		c.1362G>A	p.Ala454Ala	synonymous	Exon 11 of 23	NP_001243143.1	P13637-3
	ATP1A3	NM_001256213.2		c.1356G>A	p.Ala452Ala	synonymous	Exon 11 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.1323G>A	p.Ala441Ala	synonymous	Exon 11 of 23	ENSP00000498113.1	P13637-1
	ENSG00000285505	ENST00000644613.1		n.1323G>A		non_coding_transcript_exon	Exon 11 of 25	ENSP00000494711.1	A0A2R8YEY8
	ATP1A3	ENST00000545399.6	TSL:2	c.1362G>A	p.Ala454Ala	synonymous	Exon 11 of 23	ENSP00000444688.1	P13637-3

Frequencies

GnomAD3 genomes AF: 0.00620 AC: 943 AN: 152184 Hom.: 8 Cov.: 31

Gnomad AFR AF: 0.00154

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.00923

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0107

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00725 AC: 1824 AN: 251432 AF XY: 0.00756

Gnomad AFR exome AF: 0.00154

Gnomad AMR exome AF: 0.00127

Gnomad ASJ exome AF: 0.00149

Gnomad EAS exome AF: 0.000435

Gnomad FIN exome AF: 0.0104

Gnomad NFE exome AF: 0.0122

Gnomad OTH exome AF: 0.00603

GnomAD4 exome AF: 0.0101 AC: 14798 AN: 1461890 Hom.: 94 Cov.: 32 AF XY: 0.0100 AC XY: 7278 AN XY: 727246

African (AFR) AF: 0.00128 AC: 43 AN: 33480

American (AMR) AF: 0.00136 AC: 61 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00103 AC: 27 AN: 26136

East Asian (EAS) AF: 0.000579 AC: 23 AN: 39700

South Asian (SAS) AF: 0.00350 AC: 302 AN: 86258

European-Finnish (FIN) AF: 0.00998 AC: 533 AN: 53418

Middle Eastern (MID) AF: 0.00208 AC: 12 AN: 5768

European-Non Finnish (NFE) AF: 0.0119 AC: 13288 AN: 1112010

Other (OTH) AF: 0.00843 AC: 509 AN: 60396

GnomAD4 genome AF: 0.00620 AC: 944 AN: 152302 Hom.: 8 Cov.: 31 AF XY: 0.00606 AC XY: 451 AN XY: 74474

African (AFR) AF: 0.00154 AC: 64 AN: 41558

American (AMR) AF: 0.00157 AC: 24 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5188

South Asian (SAS) AF: 0.00311 AC: 15 AN: 4824

European-Finnish (FIN) AF: 0.00923 AC: 98 AN: 10614

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

European-Non Finnish (NFE) AF: 0.0107 AC: 727 AN: 68036

Other (OTH) AF: 0.00284 AC: 6 AN: 2112

Alfa AF: 0.00686 Hom.: 0

Bravo AF: 0.00570

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00916

EpiControl AF: 0.00877

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	-	3	not specified (3)
-	1	1	Alternating hemiplegia of childhood 2 (2)
-	-	2	Dystonia 12 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.19
CADD	Benign	11
DANN	Benign	0.65
PhyloP100		1.2
Mutation Taster		=86/14	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: rs34578730; hg19: chr19-42485768;