NM_001353812.2:c.2923T>G

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, single submitter U:1
• 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP11C	NM_001353812.2	c.2923T>G	p.Tyr975Asp	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.2923T>G	p.Tyr975Asp	missense_variant	Exon 25 of 30		NM_001353812.2	ENSP00000507250.1

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

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 14, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2932T>G (p.Y978D) alteration is located in exon 25 (coding exon 25) of the ATP11C gene. This alteration results from a T to G substitution at nucleotide position 2932, causing the tyrosine (Y) at amino acid position 978 to be replaced by an aspartic acid (D). 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	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;D;D;D
M_CAP	Pathogenic	0.48	D
MetaRNN	Pathogenic	0.83	D;D;D;D
MetaSVM	Uncertain	0.43	D
MutationAssessor	Pathogenic	3.2	.;M;M;.
PhyloP100		3.8
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-6.2	D;D;D;D
REVEL	Uncertain	0.57
Sift	Uncertain	0.0040	D;D;D;D
Sift4G	Uncertain	0.027	D;D;D;D
Polyphen		0.95, 0.94	.;P;P;.
Vest4		0.77
MutPred		0.58		.;Loss of sheet (P = 0.1158);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;