X-139745854-T-A

Variant names:

• chrX-139745854-T-A
• rs775449508
• NM_001353812.2:c.2832A>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001353812.2(ATP11C):​c.2832A>T​(p.Lys944Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000268 in 112,032 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000027 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.0000028 (0 hom. 2 hem.)
  • Failed GnomAD Quality Control
• Consequence: ATP11C NM_001353812.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.345

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.075508535).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP11C	NM_001353812.2	c.2832A>T	p.Lys944Asn	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.2832A>T	p.Lys944Asn	missense_variant	Exon 25 of 30		NM_001353812.2	ENSP00000507250.1

Frequencies

GnomAD3 genomes AF: 0.0000268 AC: 3 AN: 112032 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000973

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

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: 0.00000607 AC: 1 AN: 164851 AF XY: 0.0000186

Gnomad AFR exome AF: 0.0000805

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000278 AC: 3 AN: 1080451 Hom.: 0 Cov.: 29 AF XY: 0.00000571 AC XY: 2 AN XY: 350287

African (AFR) AF: 0.0000786 AC: 2 AN: 25461

American (AMR) AF: 0.00 AC: 0 AN: 32165

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18503

East Asian (EAS) AF: 0.00 AC: 0 AN: 29883

South Asian (SAS) AF: 0.00 AC: 0 AN: 49881

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40111

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4033

European-Non Finnish (NFE) AF: 0.00000120 AC: 1 AN: 835115

Other (OTH) AF: 0.00 AC: 0 AN: 45299

GnomAD4 genome AF: 0.0000268 AC: 3 AN: 112032 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34246

African (AFR) AF: 0.0000973 AC: 3 AN: 30845

American (AMR) AF: 0.00 AC: 0 AN: 10549

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2648

East Asian (EAS) AF: 0.00 AC: 0 AN: 3540

South Asian (SAS) AF: 0.00 AC: 0 AN: 2702

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6141

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 237

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53172

Other (OTH) AF: 0.00 AC: 0 AN: 1510

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 20, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2841A>T (p.K947N) alteration is located in exon 25 (coding exon 25) of the ATP11C gene. This alteration results from a A to T substitution at nucleotide position 2841, causing the lysine (K) at amino acid position 947 to be replaced by an asparagine (N). 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	0.25
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.026	.;T;.;.
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.74	T;T;T;T
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.076	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.030	.;N;N;.
PhyloP100		-0.34
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.19	N;N;N;N
REVEL	Benign	0.033
Sift	Benign	0.38	T;T;T;D
Sift4G	Benign	0.36	T;T;T;T
Polyphen		0.013, 0.022	.;B;B;.
Vest4		0.13
MutPred		0.35		.;Loss of ubiquitination at K947 (P = 0.0546);Loss of ubiquitination at K947 (P = 0.0546);.;
MVP		0.72
MPC		0.53
ClinPred		0.080	T
GERP RS		3.4
PromoterAI		0.0029	Neutral
Varity_R		0.30
gMVP		0.40
Mutation Taster		=59/41	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

Publications

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Other links and lift over

dbSNP: rs775449508; hg19: chrX-138828013;