X-139745763-A-C

Variant names:

• chrX-139745763-A-C
• rs944483041
• NM_001353812.2:c.2923T>G

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP3 BS2

The NM_001353812.2(ATP11C):​c.2923T>G​(p.Tyr975Asp) variant causes a missense change. The variant allele was found at a frequency of 0.0000124 in 1,207,117 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 6 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000062 (0 hom., 3 hem., cov: 23)
  • Exomes 𝑓: 0.0000073 (0 hom. 3 hem.)
• Consequence: ATP11C NM_001353812.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.77
• 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: Likely_benign. The variant received -3 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.827
• BS2: High Hemizygotes in GnomAd4 at 3 XL,Unknown gene

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.2923T>G	p.Tyr975Asp	missense	Exon 25 of 30	NP_001340741.2	A0A804HIW2
	ATP11C	NM_173694.5		c.2932T>G	p.Tyr978Asp	missense	Exon 25 of 30	NP_775965.3
	ATP11C	NM_001353811.2		c.2923T>G	p.Tyr975Asp	missense	Exon 25 of 30	NP_001340740.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP11C	ENST00000682941.1	MANE Select	c.2923T>G	p.Tyr975Asp	missense	Exon 25 of 30	ENSP00000507250.1	A0A804HIW2
	ATP11C	ENST00000327569.7	TSL:1	c.2932T>G	p.Tyr978Asp	missense	Exon 25 of 30	ENSP00000332756.3	Q8NB49-1
	ATP11C	ENST00000361648.6	TSL:1	c.2932T>G	p.Tyr978Asp	missense	Exon 25 of 29	ENSP00000355165.2	Q8NB49-3

Frequencies

GnomAD3 genomes AF: 0.0000624 AC: 7 AN: 112148 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000324

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000474

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: 0.000661

GnomAD2 exomes AF: 0.00000556 AC: 1 AN: 179770 AF XY: 0.0000155

Gnomad AFR exome AF: 0.00

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: 0.000228

GnomAD4 exome AF: 0.00000731 AC: 8 AN: 1094969 Hom.: 0 Cov.: 29 AF XY: 0.00000831 AC XY: 3 AN XY: 360959

African (AFR) AF: 0.00 AC: 0 AN: 26246

American (AMR) AF: 0.000143 AC: 5 AN: 34965

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19247

East Asian (EAS) AF: 0.00 AC: 0 AN: 30150

South Asian (SAS) AF: 0.00 AC: 0 AN: 53468

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40483

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4114

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 840352

Other (OTH) AF: 0.0000435 AC: 2 AN: 45944

GnomAD4 genome AF: 0.0000624 AC: 7 AN: 112148 Hom.: 0 Cov.: 23 AF XY: 0.0000874 AC XY: 3 AN XY: 34344

African (AFR) AF: 0.0000324 AC: 1 AN: 30875

American (AMR) AF: 0.000474 AC: 5 AN: 10559

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2659

East Asian (EAS) AF: 0.00 AC: 0 AN: 3537

South Asian (SAS) AF: 0.00 AC: 0 AN: 2700

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6154

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53227

Other (OTH) AF: 0.000661 AC: 1 AN: 1512

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000242

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.31	T
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.48	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Uncertain	0.43	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		3.8
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-6.2	D
REVEL	Uncertain	0.57
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.027	D
Polyphen		0.95	P
Vest4		0.77
MutPred		0.58		Loss of sheet (P = 0.1158)
MVP		0.91
MPC		1.4
ClinPred		0.99	D
GERP RS		6.0
PromoterAI		-0.018	Neutral
Varity_R		0.96
gMVP		0.90
Mutation Taster		=64/36	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: rs944483041; hg19: chrX-138827922;