X-120366604-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001142447.3(ATP1B4):c.143T>C(p.Val48Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0108 in 1,200,479 control chromosomes in the GnomAD database, including 644 homozygotes. There are 4,151 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V48M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.013 (52 hom., 476 hem., cov: 22)
  • Exomes 𝑓: 0.011 (592 hom. 3675 hem.)
• Consequence: ATP1B4 NM_001142447.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.235

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0014892519).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.154 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP1B4	NM_001142447.3	c.143T>C	p.Val48Ala	missense_variant	2/8	ENST00000218008.8
ATP1B4	NM_012069.5	c.143T>C	p.Val48Ala	missense_variant	2/8
ATP1B4	XM_017029381.2	c.143T>C	p.Val48Ala	missense_variant	2/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP1B4	ENST00000218008.8	c.143T>C	p.Val48Ala	missense_variant	2/8	1	NM_001142447.3	P1
ATP1B4	ENST00000361319.3	c.143T>C	p.Val48Ala	missense_variant	2/8	1
ATP1B4	ENST00000539306.5	c.143T>C	p.Val48Ala	missense_variant	2/7	2

Frequencies

GnomAD3 genomes AF: 0.0131 AC: 1435 AN: 109647 Hom.: 52 Cov.: 22 AF XY: 0.0148 AC XY: 474 AN XY: 32009

Gnomad AFR AF: 0.000998

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0614

Gnomad ASJ AF: 0.00725

Gnomad EAS AF: 0.165

Gnomad SAS AF: 0.0103

Gnomad FIN AF: 0.0122

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00129

Gnomad OTH AF: 0.0123

GnomAD3 exomes AF: 0.0303 AC: 5463 AN: 180080 Hom.: 243 AF XY: 0.0249 AC XY: 1654 AN XY: 66444

Gnomad AFR exome AF: 0.000609

Gnomad AMR exome AF: 0.0859

Gnomad ASJ exome AF: 0.00593

Gnomad EAS exome AF: 0.168

Gnomad SAS exome AF: 0.00953

Gnomad FIN exome AF: 0.0130

Gnomad NFE exome AF: 0.00298

Gnomad OTH exome AF: 0.0254

GnomAD4 exome AF: 0.0106 AC: 11546 AN: 1090779 Hom.: 592 Cov.: 29 AF XY: 0.0103 AC XY: 3675 AN XY: 356467

Gnomad4 AFR exome AF: 0.000837

Gnomad4 AMR exome AF: 0.0826

Gnomad4 ASJ exome AF: 0.00564

Gnomad4 EAS exome AF: 0.203

Gnomad4 SAS exome AF: 0.00932

Gnomad4 FIN exome AF: 0.0124

Gnomad4 NFE exome AF: 0.000852

Gnomad4 OTH exome AF: 0.0145

GnomAD4 genome AF: 0.0131 AC: 1434 AN: 109700 Hom.: 52 Cov.: 22 AF XY: 0.0148 AC XY: 476 AN XY: 32072

Gnomad4 AFR AF: 0.000996

Gnomad4 AMR AF: 0.0615

Gnomad4 ASJ AF: 0.00725

Gnomad4 EAS AF: 0.166

Gnomad4 SAS AF: 0.00991

Gnomad4 FIN AF: 0.0122

Gnomad4 NFE AF: 0.00129

Gnomad4 OTH AF: 0.0114

Alfa AF: 0.00612 Hom.: 48

Bravo AF: 0.0179

ESP6500AA AF: 0.000522 AC: 2

ESP6500EA AF: 0.000297 AC: 2

ExAC AF: 0.0251 AC: 3047

EpiCase AF: 0.000927

EpiControl AF: 0.00107

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.99	T
BayesDel_noAF	Benign	-1.1
Cadd	Benign	0.71
Dann	Benign	0.23
DEOGEN2	Benign	0.0062	T;T;.
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.53	T;T;T
MetaRNN	Benign	0.0015	T;T;T
MetaSVM	Benign	-0.94	T
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.43	T
PROVEAN	Benign	0.12	N;N;N
REVEL	Benign	0.033
Sift	Benign	0.30	T;T;T
Sift4G	Benign	0.50	T;T;T
Polyphen		0.0	B;B;B
Vest4		0.058
MPC		0.19
ClinPred		0.0069	T
GERP RS		-2.0
Varity_R		0.047
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: rs2072452; hg19: chrX-119500459; COSMIC: COSV54315303;