X-139741078-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_001353812.2(ATP11C):c.3047G>A(p.Arg1016Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000101 in 1,087,054 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.000010 (0 hom. 4 hem.)
• Consequence: ATP11C NM_001353812.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.48

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

Verdict is Likely_benign. Variant got -4 ACMG points.

• BS2: High Hemizygotes in GnomAdExome at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP11C	NM_001353812.2	c.3047G>A	p.Arg1016Gln	missense_variant	27/30	ENST00000682941.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP11C	ENST00000682941.1	c.3047G>A	p.Arg1016Gln	missense_variant	27/30		NM_001353812.2	A1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD3 exomes AF: 0.0000330 AC: 6 AN: 181563 Hom.: 0 AF XY: 0.0000301 AC XY: 2 AN XY: 66453

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000369

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000146

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000126

Gnomad NFE exome AF: 0.0000123

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000101 AC: 11 AN: 1087054 Hom.: 0 Cov.: 27 AF XY: 0.0000113 AC XY: 4 AN XY: 353452

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000286

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000996

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000124

Gnomad4 NFE exome AF: 0.00000240

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ExAC AF: 0.00000825 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 06, 2022

The c.3056G>A (p.R1019Q) alteration is located in exon 27 (coding exon 27) of the ATP11C gene. This alteration results from a G to A substitution at nucleotide position 3056, causing the arginine (R) at amino acid position 1019 to be replaced by a glutamine (Q). 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	0.17
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.17
Cadd	Benign	21
Dann	Pathogenic	1.0
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.92	D;D;D;D
M_CAP	Pathogenic	0.62	D
MetaRNN	Uncertain	0.47	T;T;T;T
MetaSVM	Uncertain	0.32	D
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.91	N;N;N;N
REVEL	Uncertain	0.64
Sift	Benign	0.16	T;T;T;D
Sift4G	Benign	0.32	T;T;T;T
Polyphen		0.99, 0.99	.;D;D;.
Vest4		0.50
MutPred		0.56		.;Loss of MoRF binding (P = 0.034);Loss of MoRF binding (P = 0.034);.;
MVP		0.99
MPC		1.4
ClinPred		0.58	D
GERP RS		3.8
Varity_R		0.45
gMVP		0.56

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs756474288; hg19: chrX-138823237; COSMIC: COSV59564357;