Genetic Variant ATP11C:p.Gln1051His (chrX-139738051-C-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_001353812.2(ATP11C):c.3153G>C(p.Gln1051His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000921 in 1,085,926 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 9.2e-7 ( 0 hom. 0 hem. )

Consequence

ATP11C
NM_001353812.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.406

Variant links:

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 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP11C	NM_001353812.2 link	c.3153G>C	p.Gln1051His	missense_variant	Exon 28 of 30	ENST00000682941.1	NP_001340741.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP11C	ENST00000682941.1 link	c.3153G>C	p.Gln1051His	missense_variant	Exon 28 of 30		NM_001353812.2	ENSP00000507250.1		A0A804HIW2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

9.21e-7

AC:

AN:

1085926

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

353504

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25946

American (AMR)

AF:

0.00

AC:

AN:

33747

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18898

East Asian (EAS)

AF:

0.00

AC:

AN:

29995

South Asian (SAS)

AF:

0.00

AC:

AN:

50825

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40180

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4066

European-Non Finnish (NFE)

AF:

0.00000120

AC:

AN:

836753

Other (OTH)

AF:

0.00

AC:

AN:

45516

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 11, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.3162G>C (p.Q1054H) alteration is located in exon 28 (coding exon 28) of the ATP11C gene. This alteration results from a G to C substitution at nucleotide position 3162, causing the glutamine (Q) at amino acid position 1054 to be replaced by a histidine (H). 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

0.81

BayesDel_addAF

Uncertain

0.040

BayesDel_noAF

Benign

-0.18

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.25

.;T;.;.

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.96

D;D;D;D

M_CAP

Pathogenic

0.55

MetaRNN

Uncertain

0.50

T;T;T;T

MetaSVM

Benign

-0.92

MutationAssessor

Uncertain

2.5

.;M;M;.

PhyloP100

0.41

PrimateAI

Uncertain

0.79

PROVEAN

Uncertain

-3.0

D;D;D;D

REVEL

Benign

0.28

Sift

Uncertain

0.020

D;D;D;D

Sift4G

Benign

0.064

T;T;T;D

Polyphen

1.0

.;D;D;.

Vest4

0.57

MutPred

0.43

.;Loss of solvent accessibility (P = 0.0238);Loss of solvent accessibility (P = 0.0238);.;

MVP

0.67

MPC

1.3

ClinPred

0.98

GERP RS

3.9

Varity_R

0.91

gMVP

0.75

Mutation Taster

=51/49

polymorphism

(source)

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

Publications

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X-139738051-C-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over