X-120366624-G-A

Position:

• chrX-120366624-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001142447.3(ATP1B4):​c.163G>A​(p.Glu55Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000915 in 1,093,116 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.1e-7 (0 hom. 1 hem.)
• Consequence: ATP1B4 NM_001142447.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.476

Genes affected

ATP1B4 (HGNC:808): (ATPase Na+/K+ transporting family member beta 4) This gene has been found in all vertebrate genomes sequenced to date. However, this gene has undergone a change in function in placental mammals compared to other species. Specifically, in fish, avian, and amphibian species, this gene encodes plasma membrane-bound beta-subunits of Na,K-ATPase. In placental mammals, the encoded protein interacts with the nuclear transcriptional coregulator SKIP and may be involved in the regulation of TGF-beta signaling. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08066121).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP1B4	NM_001142447.3	c.163G>A	p.Glu55Lys	missense_variant	2/8	ENST00000218008.8	NP_001135919.1
ATP1B4	NM_012069.5	c.163G>A	p.Glu55Lys	missense_variant	2/8		NP_036201.1
ATP1B4	XM_017029381.2	c.163G>A	p.Glu55Lys	missense_variant	2/5		XP_016884870.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP1B4	ENST00000218008.8	c.163G>A	p.Glu55Lys	missense_variant	2/8	1	NM_001142447.3	ENSP00000218008.3
ATP1B4	ENST00000361319.3	c.163G>A	p.Glu55Lys	missense_variant	2/8	1		ENSP00000355346.3
ATP1B4	ENST00000539306.5	c.163G>A	p.Glu55Lys	missense_variant	2/7	2		ENSP00000443334.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.15e-7 AC: 1 AN: 1093116 Hom.: 0 Cov.: 30 AF XY: 0.00000279 AC XY: 1 AN XY: 358764

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000185

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 03, 2024

The c.163G>A (p.E55K) alteration is located in exon 2 (coding exon 2) of the ATP1B4 gene. This alteration results from a G to A substitution at nucleotide position 163, causing the glutamic acid (E) at amino acid position 55 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	12
DANN	Benign	0.94
DEOGEN2	Benign	0.0082	T;T;.
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.78	T;T;T
M_CAP	Benign	0.0091	T
MetaRNN	Benign	0.081	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	.;N;N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.10	N;N;N
REVEL	Benign	0.060
Sift	Benign	0.16	T;T;T
Sift4G	Uncertain	0.0060	D;D;D
Polyphen		0.0	B;B;B
Vest4		0.28
MutPred		0.11		Gain of ubiquitination at E55 (P = 0.0117);Gain of ubiquitination at E55 (P = 0.0117);Gain of ubiquitination at E55 (P = 0.0117);
MVP		0.46
MPC		0.18
ClinPred		0.078	T
GERP RS		1.2
Varity_R		0.068
gMVP		0.36

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: rs2058287625; hg19: chrX-119500479;