rs1556323334

Variant names:

• chrX-139789451-G-T
• rs1556323334
• NM_001353812.2:c.1244C>A

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PS3 PM2 PP3_Strong PP5_Moderate

The NM_001353812.2(ATP11C):​c.1244C>A​(p.Thr415Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). ClinVar reports functional evidence for this variant: "SCV000883186: Well-established functional studies show a deleterious effect (https://www.ncbi.nlm.nih.gov/pubmed/26944472).".

• Frequency: Genomes: not found (cov: 23)
• Consequence: ATP11C NM_001353812.2 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 10.0
• 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: Pathogenic. The variant received 12 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000883186: Well-established functional studies show a deleterious effect (https://www.ncbi.nlm.nih.gov/pubmed/26944472).
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.967
• PP5: Variant X-139789451-G-T is Pathogenic according to our data. Variant chrX-139789451-G-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 560168.Status of the report is criteria_provided_single_submitter, 1 stars.

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.1244C>A	p.Thr415Asn	missense	Exon 13 of 30	NP_001340741.2	A0A804HIW2
	ATP11C	NM_173694.5		c.1253C>A	p.Thr418Asn	missense	Exon 13 of 30	NP_775965.3
	ATP11C	NM_001353811.2		c.1244C>A	p.Thr415Asn	missense	Exon 13 of 30	NP_001340740.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP11C	ENST00000682941.1	MANE Select	c.1244C>A	p.Thr415Asn	missense	Exon 13 of 30	ENSP00000507250.1	A0A804HIW2
	ATP11C	ENST00000327569.7	TSL:1	c.1253C>A	p.Thr418Asn	missense	Exon 13 of 30	ENSP00000332756.3	Q8NB49-1
	ATP11C	ENST00000361648.6	TSL:1	c.1253C>A	p.Thr418Asn	missense	Exon 13 of 29	ENSP00000355165.2	Q8NB49-3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
2	-	-	X-linked congenital hemolytic anemia (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.81	D
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.76	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.0	H
PhyloP100		10
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-4.8	D
REVEL	Pathogenic	0.78
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.15	B
Vest4		0.94
MutPred		0.79		Loss of phosphorylation at T414 (P = 0.0829)
MVP		0.97
MPC		0.61
ClinPred		1.0	D
GERP RS		5.8
PromoterAI		0.00020	Neutral
Varity_R		0.96
gMVP		0.98
Mutation Taster		=3/97	disease causing (ClinVar)

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: rs1556323334; hg19: chrX-138871610; COSMIC: COSV59575254; COSMIC: COSV59575254;