19-41969513-G-A

Variant names:

• chr19-41969513-G-A
• rs35272495
• NM_152296.5:c.2610C>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.2610C>T​(p.Pro870Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00204 in 1,614,140 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P870P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0074 (12 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (18 hom.)
• Consequence: ATP1A3 NM_152296.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -3.59
• Publications: 0 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 19-41969513-G-A is Benign according to our data. Variant chr19-41969513-G-A is described in ClinVar as Benign. ClinVar VariationId is 329403.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.59 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00739 (1125/152250) while in subpopulation AFR AF = 0.0216 (896/41542). AF 95% confidence interval is 0.0204. There are 12 homozygotes in GnomAd4. There are 549 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 12 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.2610C>T	p.Pro870Pro	synonymous	Exon 19 of 23	NP_689509.1
	ATP1A3	NM_001256214.2		c.2649C>T	p.Pro883Pro	synonymous	Exon 19 of 23	NP_001243143.1
	ATP1A3	NM_001256213.2		c.2643C>T	p.Pro881Pro	synonymous	Exon 19 of 23	NP_001243142.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP1A3	ENST00000648268.1	MANE Select	c.2610C>T	p.Pro870Pro	synonymous	Exon 19 of 23	ENSP00000498113.1
	ENSG00000285505	ENST00000644613.1		n.2610C>T		non_coding_transcript_exon	Exon 19 of 25	ENSP00000494711.1
	ATP1A3	ENST00000545399.6	TSL:2	c.2649C>T	p.Pro883Pro	synonymous	Exon 19 of 23	ENSP00000444688.1

Frequencies

GnomAD3 genomes AF: 0.00740 AC: 1126 AN: 152132 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.0216

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00360

Gnomad ASJ AF: 0.0395

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.00622

GnomAD2 exomes AF: 0.00364 AC: 915 AN: 251480 AF XY: 0.00294

Gnomad AFR exome AF: 0.0231

Gnomad AMR exome AF: 0.00202

Gnomad ASJ exome AF: 0.0380

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000492

Gnomad OTH exome AF: 0.00423

GnomAD4 exome AF: 0.00149 AC: 2172 AN: 1461890 Hom.: 18 Cov.: 32 AF XY: 0.00138 AC XY: 1004 AN XY: 727246

African (AFR) AF: 0.0184 AC: 617 AN: 33480

American (AMR) AF: 0.00221 AC: 99 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0357 AC: 932 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000162 AC: 14 AN: 86258

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53420

Middle Eastern (MID) AF: 0.00121 AC: 7 AN: 5768

European-Non Finnish (NFE) AF: 0.000231 AC: 257 AN: 1112010

Other (OTH) AF: 0.00406 AC: 245 AN: 60394

GnomAD4 genome AF: 0.00739 AC: 1125 AN: 152250 Hom.: 12 Cov.: 32 AF XY: 0.00738 AC XY: 549 AN XY: 74430

African (AFR) AF: 0.0216 AC: 896 AN: 41542

American (AMR) AF: 0.00360 AC: 55 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0395 AC: 137 AN: 3470

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.000353 AC: 24 AN: 68008

Other (OTH) AF: 0.00616 AC: 13 AN: 2112

Alfa AF: 0.00512 Hom.: 4

Bravo AF: 0.00831

EpiCase AF: 0.000763

EpiControl AF: 0.00101

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Dystonia 12 (3)
-	-	3	not provided (3)
-	-	2	Alternating hemiplegia of childhood 2 (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	-0.78
CADD	Benign	0.88
DANN	Benign	0.64
PhyloP100		-3.6
Mutation Taster		=98/2	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: rs35272495; hg19: chr19-42473665; COSMIC: COSV57487594;