X-139743597-T-C

Variant names:

• chrX-139743597-T-C
• NM_001353812.2:c.2992A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001353812.2(ATP11C):​c.2992A>G​(p.Ile998Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: ATP11C NM_001353812.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.16
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20106363).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP11C	NM_001353812.2	c.2992A>G	p.Ile998Val	missense_variant	Exon 26 of 30	ENST00000682941.1	NP_001340741.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP11C	ENST00000682941.1	c.2992A>G	p.Ile998Val	missense_variant	Exon 26 of 30		NM_001353812.2	ENSP00000507250.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1061184 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 334222

African (AFR) AF: 0.00 AC: 0 AN: 25573

American (AMR) AF: 0.00 AC: 0 AN: 33728

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18557

East Asian (EAS) AF: 0.00 AC: 0 AN: 29705

South Asian (SAS) AF: 0.00 AC: 0 AN: 48494

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39436

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3981

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 817113

Other (OTH) AF: 0.00 AC: 0 AN: 44597

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

X-linked congenital hemolytic anemia Uncertain:1

May 24, 2023

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.038	.;T;.;.
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.83	T;T;T;T
M_CAP	Benign	0.0099	T
MetaRNN	Benign	0.20	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.34	.;N;N;.
PhyloP100		1.2
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.65	N;N;N;N
REVEL	Benign	0.071
Sift	Benign	0.10	T;T;T;T
Sift4G	Benign	0.31	T;T;T;D
Polyphen		0.0	.;B;B;.
Vest4		0.19
MutPred		0.38		.;Gain of helix (P = 0.0854);Gain of helix (P = 0.0854);.;
MVP		0.40
MPC		0.37
ClinPred		0.28	T
GERP RS		4.4
Varity_R		0.20
gMVP		0.39
Mutation Taster		=83/17	polymorphism

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

Other links and lift over

hg19: chrX-138825756;