Genetic Variant NM_001353812.2:c.3056C>G (chrX-139741069-G-C) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001353812.2(ATP11C):c.3056C>G(p.Thr1019Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000918 in 1,089,752 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T1019M) has been classified 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

Not reported in ClinVar

Conservation

PhyloP100: 9.54

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

X-linked congenital hemolytic anemia
Inheritance: XL, Unknown Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ATP11C links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.915

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP11C	NM_001353812.2 link	c.3056C>G	p.Thr1019Arg	missense_variant	Exon 27 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.3056C>G	p.Thr1019Arg	missense_variant	Exon 27 of 30		NM_001353812.2	ENSP00000507250.1		A0A804HIW2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

9.18e-7

AC:

AN:

1089752

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

356048

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

26172

American (AMR)

AF:

0.00

AC:

AN:

34935

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19253

East Asian (EAS)

AF:

0.00

AC:

AN:

30145

South Asian (SAS)

AF:

0.00

AC:

AN:

53763

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40471

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4109

European-Non Finnish (NFE)

AF:

0.00000120

AC:

AN:

835170

Other (OTH)

AF:

0.00

AC:

AN:

45734

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.93

BayesDel_addAF

Pathogenic

0.47

BayesDel_noAF

Pathogenic

0.44

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.29

.;T;.;.

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

D;D;D;D

M_CAP

Pathogenic

0.91

MetaRNN

Pathogenic

0.91

D;D;D;D

MetaSVM

Uncertain

0.58

MutationAssessor

Pathogenic

3.2

.;M;M;.

PhyloP100

9.5

PrimateAI

Pathogenic

0.79

PROVEAN

Pathogenic

-4.8

D;D;D;D

REVEL

Pathogenic

0.80

Sift

Pathogenic

0.0

D;D;D;D

Sift4G

Pathogenic

0.0010

D;D;D;D

Polyphen

1.0

.;D;D;.

Vest4

0.86

MutPred

0.66

.;Gain of MoRF binding (P = 0.0105);Gain of MoRF binding (P = 0.0105);.;

MVP

0.95

MPC

1.4

ClinPred

1.0

GERP RS

5.5

Varity_R

0.99

gMVP

0.97

Mutation Taster

=5/95

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.22

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.22

Position offset: 25

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over