X-139745823-G-A

Variant names:

• chrX-139745823-G-A
• rs756953682
• NM_001353812.2:c.2863C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001353812.2(ATP11C):​c.2863C>T​(p.Pro955Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000223 in 1,202,634 control chromosomes in the GnomAD database, including 1 homozygotes. There are 84 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000080 (0 hom., 4 hem., cov: 23)
  • Exomes 𝑓: 0.00024 (1 hom. 80 hem.)
• Consequence: ATP11C NM_001353812.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.63
• Publications: 1 publications found

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]

ATP11C Gene-Disease associations (from GenCC):

• X-linked congenital hemolytic anemia

  Inheritance: XL, Unknown Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.093842804).
• BS2: High Hemizygotes in GnomAd4 at 4 XL,Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP11C	NM_001353812.2	c.2863C>T	p.Pro955Ser	missense_variant	Exon 25 of 30	ENST00000682941.1	NP_001340741.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP11C	ENST00000682941.1	c.2863C>T	p.Pro955Ser	missense_variant	Exon 25 of 30		NM_001353812.2	ENSP00000507250.1

Frequencies

GnomAD3 genomes AF: 0.0000804 AC: 9 AN: 111989 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00254

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000119 AC: 21 AN: 177117 AF XY: 0.0000805

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00158

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000237 AC: 259 AN: 1090594 Hom.: 1 Cov.: 29 AF XY: 0.000224 AC XY: 80 AN XY: 356930

African (AFR) AF: 0.00 AC: 0 AN: 26047

American (AMR) AF: 0.00 AC: 0 AN: 34600

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19114

East Asian (EAS) AF: 0.00850 AC: 255 AN: 29999

South Asian (SAS) AF: 0.00 AC: 0 AN: 52231

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40346

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4086

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 838419

Other (OTH) AF: 0.0000874 AC: 4 AN: 45752

GnomAD4 genome AF: 0.0000803 AC: 9 AN: 112040 Hom.: 0 Cov.: 23 AF XY: 0.000117 AC XY: 4 AN XY: 34294

African (AFR) AF: 0.00 AC: 0 AN: 30914

American (AMR) AF: 0.00 AC: 0 AN: 10568

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2651

East Asian (EAS) AF: 0.00255 AC: 9 AN: 3533

South Asian (SAS) AF: 0.00 AC: 0 AN: 2683

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6127

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 218

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53131

Other (OTH) AF: 0.00 AC: 0 AN: 1529

Alfa AF: 0.0000261 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.000132 AC: 16

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 04, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2872C>T (p.P958S) alteration is located in exon 25 (coding exon 25) of the ATP11C gene. This alteration results from a C to T substitution at nucleotide position 2872, causing the proline (P) at amino acid position 958 to be replaced by a serine (S). 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	0.26
BayesDel_addAF	Uncertain	0.020	T
BayesDel_noAF	Pathogenic	0.23
CADD	Benign	22
DANN	Benign	0.94
DEOGEN2	Benign	0.11	.;T;.;.
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.92	D;D;D;D
M_CAP	Pathogenic	0.72	D
MetaRNN	Benign	0.094	T;T;T;T
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Benign	0.17	.;N;N;.
PhyloP100		3.6
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.6	N;N;N;N
REVEL	Uncertain	0.52
Sift	Benign	0.59	T;T;T;T
Sift4G	Benign	0.73	T;T;T;T
Polyphen		0.44, 0.57	.;B;P;.
Vest4		0.44
MutPred		0.43		.;Gain of catalytic residue at P958 (P = 0.0515);Gain of catalytic residue at P958 (P = 0.0515);.;
MVP		0.98
MPC		1.2
ClinPred		0.090	T
GERP RS		6.0
PromoterAI		-0.019	Neutral
Varity_R		0.45
gMVP		0.79
Mutation Taster		=84/16	polymorphism

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: rs756953682; hg19: chrX-138827982; COSMIC: COSV59569264; COSMIC: COSV59569264;