chrX-120366604-T-C

Variant names:

• chrX-120366604-T-C
• rs2072452
• NM_001142447.3:c.143T>C

Variant summary

Our verdict is Benign. The variant received -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. 14/20 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. V48G) 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
• Publications: 7 publications found

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

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001142447.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP1B4	NM_001142447.3	MANE Select	c.143T>C	p.Val48Ala	missense	Exon 2 of 8	NP_001135919.1
	ATP1B4	NM_012069.5		c.143T>C	p.Val48Ala	missense	Exon 2 of 8	NP_036201.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP1B4	ENST00000218008.8	TSL:1 MANE Select	c.143T>C	p.Val48Ala	missense	Exon 2 of 8	ENSP00000218008.3
	ATP1B4	ENST00000361319.3	TSL:1	c.143T>C	p.Val48Ala	missense	Exon 2 of 8	ENSP00000355346.3
	ATP1B4	ENST00000955253.1		c.143T>C	p.Val48Ala	missense	Exon 2 of 7	ENSP00000625312.1

Frequencies

GnomAD3 genomes AF: 0.0131 AC: 1435 AN: 109647 Hom.: 52 Cov.: 22

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

GnomAD2 exomes AF: 0.0303 AC: 5463 AN: 180080 AF XY: 0.0249

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 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

African (AFR) AF: 0.000837 AC: 22 AN: 26283

American (AMR) AF: 0.0826 AC: 2904 AN: 35170

Ashkenazi Jewish (ASJ) AF: 0.00564 AC: 109 AN: 19332

East Asian (EAS) AF: 0.203 AC: 6113 AN: 30168

South Asian (SAS) AF: 0.00932 AC: 503 AN: 53950

European-Finnish (FIN) AF: 0.0124 AC: 500 AN: 40474

Middle Eastern (MID) AF: 0.00389 AC: 16 AN: 4109

European-Non Finnish (NFE) AF: 0.000852 AC: 712 AN: 835446

Other (OTH) AF: 0.0145 AC: 667 AN: 45847

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

African (AFR) AF: 0.000996 AC: 30 AN: 30114

American (AMR) AF: 0.0615 AC: 630 AN: 10252

Ashkenazi Jewish (ASJ) AF: 0.00725 AC: 19 AN: 2622

East Asian (EAS) AF: 0.166 AC: 574 AN: 3465

South Asian (SAS) AF: 0.00991 AC: 24 AN: 2422

European-Finnish (FIN) AF: 0.0122 AC: 72 AN: 5882

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 215

European-Non Finnish (NFE) AF: 0.00129 AC: 68 AN: 52562

Other (OTH) AF: 0.0114 AC: 17 AN: 1489

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 v4.9

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
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.53	T
MetaRNN	Benign	0.0015	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.23
PrimateAI	Benign	0.43	T
PROVEAN	Benign	0.12	N
REVEL	Benign	0.033
Sift	Benign	0.30	T
Sift4G	Benign	0.50	T
Polyphen		0.0	B
Vest4		0.058
MPC		0.19
ClinPred		0.0069	T
GERP RS		-2.0
Varity_R		0.047
gMVP		0.36
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2072452; hg19: chrX-119500459; COSMIC: COSV54315303;