X-120375426-A-G

Position:

• chrX-120375426-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001142447.3(ATP1B4):​c.617A>G​(p.Tyr206Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 21)
• Consequence: ATP1B4 NM_001142447.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.82

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.872

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP1B4	NM_001142447.3	c.617A>G	p.Tyr206Cys	missense_variant	5/8	ENST00000218008.8	NP_001135919.1
ATP1B4	NM_012069.5	c.605A>G	p.Tyr202Cys	missense_variant	5/8		NP_036201.1
ATP1B4	XM_017029381.2	c.617A>G	p.Tyr206Cys	missense_variant	5/5		XP_016884870.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP1B4	ENST00000218008.8	c.617A>G	p.Tyr206Cys	missense_variant	5/8	1	NM_001142447.3	ENSP00000218008.3
ATP1B4	ENST00000361319.3	c.605A>G	p.Tyr202Cys	missense_variant	5/8	1		ENSP00000355346.3
ATP1B4	ENST00000539306.5	c.488A>G	p.Tyr163Cys	missense_variant	4/7	2		ENSP00000443334.1

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 21

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

Sep 10, 2024

The c.617A>G (p.Y206C) alteration is located in exon 5 (coding exon 5) of the ATP1B4 gene. This alteration results from a A to G substitution at nucleotide position 617, causing the tyrosine (Y) at amino acid position 206 to be replaced by a cysteine (C). 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	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T;T;.
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.92	D;D;D
M_CAP	Pathogenic	0.63	D
MetaRNN	Pathogenic	0.87	D;D;D
MetaSVM	Benign	-0.43	T
MutationAssessor	Pathogenic	3.1	.;M;.
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-7.3	D;D;D
REVEL	Uncertain	0.40
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.89
MutPred		0.49		.;Loss of phosphorylation at Y206 (P = 0.0686);.;
MVP		0.80
MPC		0.74
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.90
gMVP		0.89

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-119509281;