X-139738003-C-T

Variant names:

• chrX-139738003-C-T
• rs1295591659
• NM_001353812.2:c.3201G>A

Variant summary

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

The NM_001353812.2(ATP11C):​c.3201G>A​(p.Trp1067*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000916 in 1,091,754 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.2e-7 (0 hom. 1 hem.)
• Consequence: ATP11C NM_001353812.2 stop_gained
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 7.57
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001353812.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP11C	NM_001353812.2	MANE Select	c.3201G>A	p.Trp1067*	stop_gained	Exon 28 of 30	NP_001340741.2	A0A804HIW2
	ATP11C	NM_173694.5		c.3210G>A	p.Trp1070*	stop_gained	Exon 28 of 30	NP_775965.3
	ATP11C	NM_001353811.2		c.3201G>A	p.Trp1067*	stop_gained	Exon 28 of 30	NP_001340740.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP11C	ENST00000682941.1	MANE Select	c.3201G>A	p.Trp1067*	stop_gained	Exon 28 of 30	ENSP00000507250.1	A0A804HIW2
	ATP11C	ENST00000327569.7	TSL:1	c.3210G>A	p.Trp1070*	stop_gained	Exon 28 of 30	ENSP00000332756.3	Q8NB49-1
	ATP11C	ENST00000361648.6	TSL:1	c.3210G>A	p.Trp1070*	stop_gained	Exon 28 of 29	ENSP00000355165.2	Q8NB49-3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD2 exomes AF: 0.00000553 AC: 1 AN: 180754 AF XY: 0.0000152

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000372

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 AF: 9.16e-7 AC: 1 AN: 1091754 Hom.: 0 Cov.: 28 AF XY: 0.00000279 AC XY: 1 AN XY: 358168

African (AFR) AF: 0.00 AC: 0 AN: 26185

American (AMR) AF: 0.0000286 AC: 1 AN: 34984

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19229

East Asian (EAS) AF: 0.00 AC: 0 AN: 30098

South Asian (SAS) AF: 0.00 AC: 0 AN: 53404

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40413

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4106

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 837512

Other (OTH) AF: 0.00 AC: 0 AN: 45823

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	1	-	ATP11C-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	38
DANN	Uncertain	1.0
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		7.6
Vest4		0.43
ClinPred		0.98	D
GERP RS		5.8
Mutation Taster		=146/54	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1295591659; hg19: chrX-138820162;