X-139745781-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001353812.2(ATP11C):c.2905G>A(p.Val969Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00495 in 1,206,478 control chromosomes in the GnomAD database, including 177 homozygotes. There are 1,552 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.026 (101 hom., 741 hem., cov: 23)
  • Exomes 𝑓: 0.0028 (76 hom. 811 hem.)
• Consequence: ATP11C NM_001353812.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.96

Genes affected

ATP11C (HGNC:13554): (ATPase phospholipid transporting 11C) Enables phosphatidylethanolamine flippase activity and phosphatidylserine flippase activity. Predicted to be involved in phospholipid translocation; positive regulation of B cell differentiation; and pre-B cell differentiation. Located in endoplasmic reticulum and plasma membrane. Is integral component of plasma membrane. Implicated in X-linked congenital hemolytic anemia. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0055324733).
• BP6: Variant X-139745781-C-T is Benign according to our data. Variant chrX-139745781-C-T is described in ClinVar as [Benign]. Clinvar id is 783916.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0846 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP11C	NM_001353812.2	c.2905G>A	p.Val969Met	missense_variant	25/30	ENST00000682941.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP11C	ENST00000682941.1	c.2905G>A	p.Val969Met	missense_variant	25/30		NM_001353812.2	A1

Frequencies

GnomAD3 genomes AF: 0.0256 AC: 2864 AN: 112079 Hom.: 99 Cov.: 23 AF XY: 0.0214 AC XY: 735 AN XY: 34287

Gnomad AFR AF: 0.0872

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0105

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00111

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0126

Gnomad NFE AF: 0.000657

Gnomad OTH AF: 0.0192

GnomAD3 exomes AF: 0.00754 AC: 1361 AN: 180574 Hom.: 53 AF XY: 0.00446 AC XY: 291 AN XY: 65314

Gnomad AFR exome AF: 0.0923

Gnomad AMR exome AF: 0.00428

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000108

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000482

Gnomad OTH exome AF: 0.00271

GnomAD4 exome AF: 0.00284 AC: 3104 AN: 1094346 Hom.: 76 Cov.: 29 AF XY: 0.00225 AC XY: 811 AN XY: 360314

Gnomad4 AFR exome AF: 0.0895

Gnomad4 AMR exome AF: 0.00520

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000187

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000302

Gnomad4 OTH exome AF: 0.00634

GnomAD4 genome AF: 0.0256 AC: 2872 AN: 112132 Hom.: 101 Cov.: 23 AF XY: 0.0216 AC XY: 741 AN XY: 34350

Gnomad4 AFR AF: 0.0874

Gnomad4 AMR AF: 0.0104

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00111

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000657

Gnomad4 OTH AF: 0.0190

Alfa AF: 0.00182 Hom.: 71

Bravo AF: 0.0297

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000692 AC: 2

ESP6500AA AF: 0.0918 AC: 352

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00863 AC: 1047

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

ATP11C-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 23, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.29
Cadd	Benign	19
Dann	Uncertain	1.0
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.91	D;D;D;D
MetaRNN	Benign	0.0055	T;T;T;T
MetaSVM	Benign	-0.76	T
MutationTaster	Benign	0.0019	P;P;P;P;P
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-2.2	N;N;N;N
REVEL	Uncertain	0.40
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D
Polyphen		0.96, 0.97	.;D;D;.
Vest4		0.29
MVP		0.73
MPC		0.58
ClinPred		0.025	T
GERP RS		6.0
Varity_R		0.61
gMVP		0.64

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs55724992; hg19: chrX-138827940; COSMIC: COSV59560492; COSMIC: COSV59560492;