chr19-41985095-C-T

Variant names:

• chr19-41985095-C-T
• rs149898088
• NM_152296.5:c.816G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_152296.5(ATP1A3):​c.816G>A​(p.Thr272Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00129 in 1,613,872 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (10 hom.)
• Consequence: ATP1A3 NM_152296.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -4.02
• 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.32).
• BP6: Variant 19-41985095-C-T is Benign according to our data. Variant chr19-41985095-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 468607.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.02 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00146 (223/152342) while in subpopulation NFE AF = 0.00169 (115/68034). AF 95% confidence interval is 0.00144. There are 0 homozygotes in GnomAd4. There are 116 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 10 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.816G>A	p.Thr272Thr	synonymous	Exon 8 of 23	NP_689509.1	P13637-1
	ATP1A3	NM_001256214.2		c.855G>A	p.Thr285Thr	synonymous	Exon 8 of 23	NP_001243143.1	P13637-3
	ATP1A3	NM_001256213.2		c.849G>A	p.Thr283Thr	synonymous	Exon 8 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.816G>A	p.Thr272Thr	synonymous	Exon 8 of 23	ENSP00000498113.1	P13637-1
	ENSG00000285505	ENST00000644613.1		n.816G>A		non_coding_transcript_exon	Exon 8 of 25	ENSP00000494711.1	A0A2R8YEY8
	ATP1A3	ENST00000545399.6	TSL:2	c.855G>A	p.Thr285Thr	synonymous	Exon 8 of 23	ENSP00000444688.1	P13637-3

Frequencies

GnomAD3 genomes AF: 0.00147 AC: 224 AN: 152224 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000820

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.0115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00169

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00151 AC: 378 AN: 249866 AF XY: 0.00144

Gnomad AFR exome AF: 0.000498

Gnomad AMR exome AF: 0.00113

Gnomad ASJ exome AF: 0.0130

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.000187

Gnomad NFE exome AF: 0.00136

Gnomad OTH exome AF: 0.00262

GnomAD4 exome AF: 0.00127 AC: 1860 AN: 1461530 Hom.: 10 Cov.: 32 AF XY: 0.00128 AC XY: 930 AN XY: 727032

African (AFR) AF: 0.000926 AC: 31 AN: 33480

American (AMR) AF: 0.00103 AC: 46 AN: 44660

Ashkenazi Jewish (ASJ) AF: 0.0116 AC: 304 AN: 26116

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39690

South Asian (SAS) AF: 0.000928 AC: 80 AN: 86178

European-Finnish (FIN) AF: 0.000262 AC: 14 AN: 53402

Middle Eastern (MID) AF: 0.00382 AC: 22 AN: 5766

European-Non Finnish (NFE) AF: 0.00112 AC: 1246 AN: 1111874

Other (OTH) AF: 0.00192 AC: 116 AN: 60364

GnomAD4 genome AF: 0.00146 AC: 223 AN: 152342 Hom.: 0 Cov.: 32 AF XY: 0.00156 AC XY: 116 AN XY: 74500

African (AFR) AF: 0.000818 AC: 34 AN: 41566

American (AMR) AF: 0.00131 AC: 20 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0115 AC: 40 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.000828 AC: 4 AN: 4830

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10630

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00169 AC: 115 AN: 68034

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

Alfa AF: 0.00227 Hom.: 1

Bravo AF: 0.00141

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00191

EpiControl AF: 0.00172

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	-	3	Dystonia 12 (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)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.32
CADD	Benign	5.9
DANN	Benign	0.86
PhyloP100		-4.0
Mutation Taster		=99/1	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: rs149898088; hg19: chr19-42489247;