Genetic Variant ATP6AP1L:n.1499G>C (chr5-82312653-G-C) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The ENST00000380167.8(ATP6AP1L):n.1499G>C variant causes a non coding transcript exon change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,455,028 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

ATP6AP1L
ENST00000380167.8 non_coding_transcript_exon

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.80

Variant links:

Genes affected

ATP6AP1L (HGNC:28091): (ATPase H+ transporting accessory protein 1 like (pseudogene)) Predicted to be involved in regulation of cellular pH. Predicted to be integral component of membrane. Predicted to be part of plasma membrane proton-transporting V-type ATPase complex. [provided by Alliance of Genome Resources, Apr 2022]

ATP6AP1L links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.968

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank
ATP6AP1L	NR_169870.1 link	n.2144G>C	non_coding_transcript_exon_variant	Exon 11 of 12
ATP6AP1L	NR_172106.1 link	n.1738G>C	non_coding_transcript_exon_variant	Exon 9 of 10
ATP6AP1L	NR_172107.1 link	n.2238G>C	non_coding_transcript_exon_variant	Exon 10 of 11

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL
ATP6AP1L	ENST00000380167.8 link	n.1499G>C	non_coding_transcript_exon_variant	Exon 9 of 10	2
ATP6AP1L	ENST00000508366.5 link	n.1392G>C	non_coding_transcript_exon_variant	Exon 2 of 8	2
ATP6AP1L	ENST00000514672.1 link	n.215G>C	non_coding_transcript_exon_variant	Exon 2 of 3	2
ATP6AP1L	ENST00000643922.1 link	n.526G>C	non_coding_transcript_exon_variant	Exon 6 of 7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.87e-7

AC:

AN:

1455028

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

723718

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

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

Oct 30, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.174G>C (p.W58C) alteration is located in exon 3 (coding exon 3) of the ATP6AP1L gene. This alteration results from a G to C substitution at nucleotide position 174, causing the tryptophan (W) at amino acid position 58 to be replaced by a cysteine (C). 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

0.66

BayesDel_addAF

Pathogenic

0.46

BayesDel_noAF

Pathogenic

0.42

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.45

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.91

M_CAP

Benign

0.024

MetaRNN

Pathogenic

0.97

MetaSVM

Uncertain

0.25

MutationAssessor

Uncertain

2.9

PrimateAI

Uncertain

0.53

PROVEAN

Pathogenic

-13

REVEL

Uncertain

0.62

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.79

MutPred

0.85

Loss of MoRF binding (P = 0.025);

MVP

0.12

ClinPred

1.0

GERP RS

5.7

Varity_R

0.97

gMVP

0.85

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over