chr19-41966831-A-G

Position:

• chr19-41966831-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_152296.5(ATP1A3):​c.*106T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00291 in 1,544,634 control chromosomes in the GnomAD database, including 61 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (35 hom., cov: 28)
  • Exomes 𝑓: 0.0019 (26 hom.)
• Consequence: ATP1A3 NM_152296.5 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.619

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 19-41966831-A-G is Benign according to our data. Variant chr19-41966831-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 329399.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0119 (1808/151308) while in subpopulation AFR AF= 0.0381 (1564/41076). AF 95% confidence interval is 0.0365. There are 35 homozygotes in gnomad4. There are 885 alleles in male gnomad4 subpopulation. Median coverage is 28. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1808 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP1A3	NM_152296.5	c.*106T>C		3_prime_UTR_variant	23/23	ENST00000648268.1
ATP1A3	NM_001256213.2	c.*106T>C		3_prime_UTR_variant	23/23
ATP1A3	NM_001256214.2	c.*106T>C		3_prime_UTR_variant	23/23
ATP1A3	XM_047438862.1	c.*106T>C		3_prime_UTR_variant	23/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP1A3	ENST00000648268.1	c.*106T>C		3_prime_UTR_variant	23/23		NM_152296.5

Frequencies

GnomAD3 genomes AF: 0.0119 AC: 1794 AN: 151196 Hom.: 34 Cov.: 28

Gnomad AFR AF: 0.0378

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00443

Gnomad ASJ AF: 0.0379

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000209

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000383

Gnomad OTH AF: 0.00965

GnomAD3 exomes AF: 0.00513 AC: 763 AN: 148714 Hom.: 7 AF XY: 0.00465 AC XY: 367 AN XY: 78968

Gnomad AFR exome AF: 0.0402

Gnomad AMR exome AF: 0.00297

Gnomad ASJ exome AF: 0.0365

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000177

Gnomad FIN exome AF: 0.0000678

Gnomad NFE exome AF: 0.000795

Gnomad OTH exome AF: 0.00589

GnomAD4 exome AF: 0.00193 AC: 2692 AN: 1393326 Hom.: 26 Cov.: 34 AF XY: 0.00177 AC XY: 1218 AN XY: 686994

Gnomad4 AFR exome AF: 0.0359

Gnomad4 AMR exome AF: 0.00311

Gnomad4 ASJ exome AF: 0.0347

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000228

Gnomad4 FIN exome AF: 0.0000207

Gnomad4 NFE exome AF: 0.000227

Gnomad4 OTH exome AF: 0.00537

GnomAD4 genome AF: 0.0119 AC: 1808 AN: 151308 Hom.: 35 Cov.: 28 AF XY: 0.0120 AC XY: 885 AN XY: 73926

Gnomad4 AFR AF: 0.0381

Gnomad4 AMR AF: 0.00442

Gnomad4 ASJ AF: 0.0379

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000383

Gnomad4 OTH AF: 0.00955

Alfa AF: 0.00796 Hom.: 4

Bravo AF: 0.0141

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Alternating hemiplegia of childhood 2 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Dystonia 12 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 17, 2018

- -

Developmental and epileptic encephalopathy 99 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

Cerebellar ataxia-areflexia-pes cavus-optic atrophy-sensorineural hearing loss syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	2.1
DANN	Benign	0.10

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

Publications

LitVar

Other links and lift over

dbSNP: rs180885057; hg19: chr19-42470983;