X-120370765-A-T

Position:

• chrX-120370765-A-T

Variant summary

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

The NM_001142447.3(ATP1B4):​c.379A>T​(p.Ile127Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/20 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)
• Consequence: ATP1B4 NM_001142447.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.01

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=0.10307872).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP1B4	NM_001142447.3	c.379A>T	p.Ile127Phe	missense_variant	3/8	ENST00000218008.8	NP_001135919.1
ATP1B4	NM_012069.5	c.367A>T	p.Ile123Phe	missense_variant	3/8		NP_036201.1
ATP1B4	XM_017029381.2	c.379A>T	p.Ile127Phe	missense_variant	3/5		XP_016884870.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP1B4	ENST00000218008.8	c.379A>T	p.Ile127Phe	missense_variant	3/8	1	NM_001142447.3	ENSP00000218008.3
ATP1B4	ENST00000361319.3	c.367A>T	p.Ile123Phe	missense_variant	3/8	1		ENSP00000355346.3
ATP1B4	ENST00000539306.5	c.329-341A>T		intron_variant		2		ENSP00000443334.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

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

Nov 20, 2024

The c.379A>T (p.I127F) alteration is located in exon 3 (coding exon 3) of the ATP1B4 gene. This alteration results from a A to T substitution at nucleotide position 379, causing the isoleucine (I) at amino acid position 127 to be replaced by a phenylalanine (F). 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	0.22
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	14
DANN	Benign	0.19
DEOGEN2	Benign	0.0060	T;.
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.73	T;T
M_CAP	Benign	0.0051	T
MetaRNN	Benign	0.10	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-2.6	N;.
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	5.1	N;N
REVEL	Benign	0.090
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0030	B;B
Vest4		0.27
MutPred		0.55		Loss of catalytic residue at I127 (P = 0.1313);.;
MVP		0.87
MPC		0.25
ClinPred		0.55	D
GERP RS		4.2
Varity_R		0.31
gMVP		0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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-119504620;