chrX-139741078-C-A

Variant names:

• chrX-139741078-C-A
• rs756474288
• NM_001353812.2:c.3047G>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001353812.2(ATP11C):​c.3047G>T​(p.Arg1016Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000184 in 1,087,058 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic 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. R1016Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000018 (0 hom. 1 hem.)
• Consequence: ATP11C NM_001353812.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.48
• Publications: 0 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.827

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP11C	NM_001353812.2	c.3047G>T	p.Arg1016Leu	missense_variant	Exon 27 of 30	ENST00000682941.1	NP_001340741.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP11C	ENST00000682941.1	c.3047G>T	p.Arg1016Leu	missense_variant	Exon 27 of 30		NM_001353812.2	ENSP00000507250.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000184 AC: 2 AN: 1087058 Hom.: 0 Cov.: 27 AF XY: 0.00000283 AC XY: 1 AN XY: 353456

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 26132

American (AMR) AF: 0.00 AC: 0 AN: 35002

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19236

East Asian (EAS) AF: 0.00 AC: 0 AN: 30135

South Asian (SAS) AF: 0.00 AC: 0 AN: 53761

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40468

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4100

European-Non Finnish (NFE) AF: 0.00000240 AC: 2 AN: 832585

Other (OTH) AF: 0.00 AC: 0 AN: 45639

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	.;T;.;.
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.97	D;D;D;D
M_CAP	Pathogenic	0.72	D
MetaRNN	Pathogenic	0.83	D;D;D;D
MetaSVM	Uncertain	0.31	D
MutationAssessor	Benign	1.7	.;L;L;.
PhyloP100		2.5
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-2.9	D;D;D;D
REVEL	Pathogenic	0.71
Sift	Benign	0.38	T;T;T;D
Sift4G	Benign	0.62	T;T;T;D
Polyphen		0.96, 0.97	.;P;D;.
Vest4		0.64
MutPred		0.59		.;Loss of MoRF binding (P = 0.0386);Loss of MoRF binding (P = 0.0386);.;
MVP		1.0
MPC		1.5
ClinPred		0.99	D
GERP RS		3.8
Varity_R		0.70
gMVP		0.73
Mutation Taster		=45/55	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs756474288; hg19: chrX-138823237;