chr19-41966810-T-G

Variant names:

• chr19-41966810-T-G
• rs782239785
• NM_152296.5:c.*127A>C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4 BP6_Very_Strong

The NM_152296.5(ATP1A3):​c.*127A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.082 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0035 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ATP1A3 NM_152296.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.112
• 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.254).
• BP6: Variant 19-41966810-T-G is Benign according to our data. Variant chr19-41966810-T-G is described in ClinVar as Benign. ClinVar VariationId is 1263673.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.*127A>C		3_prime_UTR	Exon 23 of 23	NP_689509.1	P13637-1
	ATP1A3	NM_001256214.2		c.*127A>C		3_prime_UTR	Exon 23 of 23	NP_001243143.1	P13637-3
	ATP1A3	NM_001256213.2		c.*127A>C		3_prime_UTR	Exon 23 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.*127A>C		3_prime_UTR	Exon 23 of 23	ENSP00000498113.1	P13637-1
	ENSG00000285505	ENST00000644613.1		n.3013+439A>C		intron	N/A	ENSP00000494711.1	A0A2R8YEY8
	ATP1A3	ENST00000545399.6	TSL:2	c.*127A>C		3_prime_UTR	Exon 23 of 23	ENSP00000444688.1	P13637-3

Frequencies

GnomAD3 genomes AF: 0.0818 AC: 2945 AN: 36018 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.0836

Gnomad AMI AF: 0.0702

Gnomad AMR AF: 0.0632

Gnomad ASJ AF: 0.0913

Gnomad EAS AF: 0.0892

Gnomad SAS AF: 0.0452

Gnomad FIN AF: 0.0520

Gnomad MID AF: 0.140

Gnomad NFE AF: 0.0889

Gnomad OTH AF: 0.101

GnomAD2 exomes AF: 0.0189 AC: 1924 AN: 101968 AF XY: 0.0170

Gnomad AFR exome AF: 0.00239

Gnomad AMR exome AF: 0.000592

Gnomad ASJ exome AF: 0.00264

Gnomad EAS exome AF: 0.00350

Gnomad FIN exome AF: 0.162

Gnomad NFE exome AF: 0.0104

Gnomad OTH exome AF: 0.00859

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00353 AC: 2591 AN: 733562 Hom.: 0 Cov.: 26 AF XY: 0.00345 AC XY: 1246 AN XY: 361216

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000296 AC: 6 AN: 20274

American (AMR) AF: 0.000325 AC: 8 AN: 24602

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 19 AN: 16538

East Asian (EAS) AF: 0.000336 AC: 9 AN: 26748

South Asian (SAS) AF: 0.00332 AC: 108 AN: 32516

European-Finnish (FIN) AF: 0.0628 AC: 1933 AN: 30798

Middle Eastern (MID) AF: 0.00124 AC: 3 AN: 2420

European-Non Finnish (NFE) AF: 0.000841 AC: 460 AN: 546838

Other (OTH) AF: 0.00137 AC: 45 AN: 32828

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0818 AC: 2951 AN: 36068 Hom.: 0 Cov.: 0 AF XY: 0.0791 AC XY: 1364 AN XY: 17244

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0838 AC: 779 AN: 9298

American (AMR) AF: 0.0637 AC: 207 AN: 3250

Ashkenazi Jewish (ASJ) AF: 0.0913 AC: 82 AN: 898

East Asian (EAS) AF: 0.0884 AC: 110 AN: 1244

South Asian (SAS) AF: 0.0462 AC: 47 AN: 1018

European-Finnish (FIN) AF: 0.0520 AC: 123 AN: 2366

Middle Eastern (MID) AF: 0.130 AC: 6 AN: 46

European-Non Finnish (NFE) AF: 0.0889 AC: 1539 AN: 17304

Other (OTH) AF: 0.101 AC: 42 AN: 416

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0388 Hom.: 0

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_noAF	Benign	-0.89
CADD	Benign	8.5
DANN	Benign	0.43
PhyloP100		0.11
Mutation Taster		=100/0	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: rs782239785; hg19: chr19-42470962; COSMIC: COSV57484779;