Genetic Variant ATP11A:p.Arg147Leu (chr13-112810725-G-T) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_015205.3(ATP11A):c.440G>T(p.Arg147Leu) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. R147Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Consequence

ATP11A
NM_015205.3 missense, splice_region

Scores

Splicing: ADA: 0.06742

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.88

Publications

1 publications found

Variant links:

Genes affected

ATP11A (HGNC:13552): (ATPase phospholipid transporting 11A) The protein encoded by this gene is an integral membrane ATPase. The encoded protein is probably phosphorylated in its intermediate state and likely drives the transport of ions such as calcium across membranes. [provided by RefSeq, Apr 2022]

ATP11A Gene-Disease associations (from GenCC):

auditory neuropathy, autosomal dominant 2
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
autosomal dominant nonsyndromic hearing loss
Inheritance: AD Classification: MODERATE Submitted by: ClinGen
complex neurodevelopmental disorder
Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
hearing loss, autosomal dominant 84
Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
leukodystrophy, hypomyelinating, 24
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ATP11A links:

ENSG00000303208 (HGNC:):

ENSG00000303208 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.775

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015205.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ATP11A	NM_015205.3	MANE Select	c.440G>T	p.Arg147Leu	missense splice_region	Exon 5 of 30	NP_056020.2	P98196
ATP11A	NM_001405661.1		c.440G>T	p.Arg147Leu	missense splice_region	Exon 5 of 29	NP_001392590.1
ATP11A	NM_032189.4		c.440G>T	p.Arg147Leu	missense splice_region	Exon 5 of 29	NP_115565.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ATP11A	ENST00000375645.8	TSL:5 MANE Select	c.440G>T	p.Arg147Leu	missense splice_region	Exon 5 of 30	ENSP00000364796.3	P98196
ATP11A	ENST00000418678.5	TSL:1	c.362G>T	p.Arg121Leu	missense splice_region	Exon 4 of 23	ENSP00000396374.1	H0Y547
ATP11A	ENST00000375630.6	TSL:5	c.440G>T	p.Arg147Leu	missense splice_region	Exon 5 of 29	ENSP00000364781.2	E9PEJ6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.16

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.61

Eigen

Benign

0.10

Eigen_PC

Benign

0.072

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

0.98

M_CAP

Uncertain

0.20

MetaRNN

Pathogenic

0.78

MetaSVM

Uncertain

0.67

MutationAssessor

Uncertain

2.6

PhyloP100

4.9

PrimateAI

Uncertain

0.78

PROVEAN

Uncertain

-3.6

REVEL

Pathogenic

0.69

Sift

Benign

0.047

Sift4G

Benign

0.19

Polyphen

0.28

Vest4

0.76

MutPred

0.60

Gain of catalytic residue at V152 (P = 0.0095)

MVP

0.77

MPC

0.47

ClinPred

0.95

GERP RS

4.6

Varity_R

0.51

gMVP

0.75

Mutation Taster

=62/38

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.067

dbscSNV1_RF

Benign

0.22

SpliceAI score (max)

0.030

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over