3-182820277-T-G

Variant names:

• chr3-182820277-T-G
• rs141226430
• NM_014616.3:c.45T>G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_014616.3(ATP11B):​c.45T>G​(p.His15Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000371 in 1,613,894 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00049 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00036 (1 hom.)
• Consequence: ATP11B NM_014616.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.46

Genes affected

ATP11B (HGNC:13553): (ATPase phospholipid transporting 11B (putative)) P-type ATPases, such as ATP11B, are phosphorylated in their intermediate state and drive uphill transport of ions across membranes. Several subfamilies of P-type ATPases have been identified. One subfamily transports heavy metal ions, such as Cu(2+) or Cd(2+). Another subfamily transports non-heavy metal ions, such as H(+), Na(+), K(+), or Ca(+). A third subfamily transports amphipaths, such as phosphatidylserine.[supplied by OMIM, Feb 2005]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.006976366).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP11B	NM_014616.3	c.45T>G	p.His15Gln	missense_variant	Exon 2 of 30	ENST00000323116.10	NP_055431.1
ATP11B	XM_047447784.1	c.45T>G	p.His15Gln	missense_variant	Exon 2 of 30		XP_047303740.1
ATP11B	XM_011512593.3	c.45T>G	p.His15Gln	missense_variant	Exon 2 of 31		XP_011510895.1
ATP11B	XM_011512594.3	c.45T>G	p.His15Gln	missense_variant	Exon 2 of 30		XP_011510896.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP11B	ENST00000323116.10	c.45T>G	p.His15Gln	missense_variant	Exon 2 of 30	2	NM_014616.3	ENSP00000321195.5
ATP11B	ENST00000493826.1	c.45T>G	p.His15Gln	missense_variant	Exon 2 of 6	1		ENSP00000419032.1

Frequencies

GnomAD3 genomes AF: 0.000499 AC: 76 AN: 152226 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00196

Gnomad ASJ AF: 0.00750

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000736 AC: 185 AN: 251472 Hom.: 0 AF XY: 0.000662 AC XY: 90 AN XY: 135912

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00150

Gnomad ASJ exome AF: 0.00853

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000588

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000158

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.000358 AC: 523 AN: 1461550 Hom.: 1 Cov.: 30 AF XY: 0.000366 AC XY: 266 AN XY: 727122

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00132

Gnomad4 ASJ exome AF: 0.00968

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000499

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000828

Gnomad4 OTH exome AF: 0.00103

GnomAD4 genome AF: 0.000492 AC: 75 AN: 152344 Hom.: 0 Cov.: 32 AF XY: 0.000537 AC XY: 40 AN XY: 74492

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.00196

Gnomad4 ASJ AF: 0.00750

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000975 Hom.: 0

Bravo AF: 0.000714

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.000511 AC: 62

EpiCase AF: 0.000327

EpiControl AF: 0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 07, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.45T>G (p.H15Q) alteration is located in exon 2 (coding exon 2) of the ATP11B gene. This alteration results from a T to G substitution at nucleotide position 45, causing the histidine (H) at amino acid position 15 to be replaced by a glutamine (Q). 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	0.11
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	21
DANN	Benign	0.93
DEOGEN2	Benign	0.0093	T;T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.036
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.0070	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.40	N;.
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-1.1	N;N
REVEL	Benign	0.20
Sift	Benign	0.13	T;T
Sift4G	Benign	0.49	T;T
Polyphen		0.33	B;.
Vest4		0.32
MutPred		0.21		Loss of catalytic residue at H15 (P = 0.0789);Loss of catalytic residue at H15 (P = 0.0789);
MVP		0.93
MPC		0.80
ClinPred		0.024	T
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.11
gMVP		0.49

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: rs141226430; hg19: chr3-182538065;