Genetic Variant ATP5F1B:p.Tyr499Cys (chr12-56638417-T-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001686.4(ATP5F1B):c.1496A>G(p.Tyr499Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000000686 in 1,457,312 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

ATP5F1B
NM_001686.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.89

Variant links:

Genes affected

ATP5F1B (HGNC:830): (ATP synthase F1 subunit beta) This gene encodes a subunit of mitochondrial ATP synthase. Mitochondrial ATP synthase catalyzes ATP synthesis, utilizing an electrochemical gradient of protons across the inner membrane during oxidative phosphorylation. ATP synthase is composed of two linked multi-subunit complexes: the soluble catalytic core, F1, and the membrane-spanning component, Fo, comprising the proton channel. The catalytic portion of mitochondrial ATP synthase consists of 5 different subunits (alpha, beta, gamma, delta, and epsilon) assembled with a stoichiometry of 3 alpha, 3 beta, and a single representative of the other 3. The proton channel consists of three main subunits (a, b, c). This gene encodes the beta subunit of the catalytic core. [provided by RefSeq, Jul 2008]

ATP5F1B links:

BAZ2A (HGNC:962): (bromodomain adjacent to zinc finger domain 2A) Enables histone binding activity. Contributes to RNA polymerase I core promoter sequence-specific DNA binding activity. Predicted to be involved in DNA methylation; histone deacetylation; and negative regulation of macromolecule metabolic process. Predicted to act upstream of or within chromatin organization and histone modification. Located in cytosol and nuclear speck. [provided by Alliance of Genome Resources, Apr 2022]

BAZ2A links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 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
ATP5F1B	NM_001686.4 link	c.1496A>G	p.Tyr499Cys	missense_variant	Exon 10 of 10	ENST00000262030.8	NP_001677.2	P06576V9HW31
BAZ2A	XM_047428142.1 link	c.-1559A>G		upstream_gene_variant			XP_047284098.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ATP5F1B	ENST00000262030.8 link	c.1496A>G	p.Tyr499Cys	missense_variant	Exon 10 of 10	1	NM_001686.4	ENSP00000262030.3	P06576
ATP5F1B	ENST00000547808.5 link	n.664A>G		non_coding_transcript_exon_variant	Exon 5 of 5	5
ATP5F1B	ENST00000548474.2 link	n.207A>G		non_coding_transcript_exon_variant	Exon 3 of 3	3
ATP5F1B	ENST00000551182.1 link	n.320A>G		non_coding_transcript_exon_variant	Exon 2 of 2	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1457312

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

725090

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.02e-7

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

Jan 23, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1496A>G (p.Y499C) alteration is located in exon 10 (coding exon 10) of the ATP5B gene. This alteration results from a A to G substitution at nucleotide position 1496, causing the tyrosine (Y) at amino acid position 499 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

Benign

0.089

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Uncertain

0.020

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.43

Eigen

Benign

0.069

Eigen_PC

Uncertain

0.22

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.99

M_CAP

Benign

0.020

MetaRNN

Uncertain

0.54

MetaSVM

Benign

-0.41

MutationAssessor

Benign

1.5

PrimateAI

Pathogenic

0.83

PROVEAN

Uncertain

-3.1

REVEL

Uncertain

0.50

Sift

Benign

0.052

Sift4G

Benign

0.10

Polyphen

0.0050

Vest4

0.77

MutPred

0.41

Gain of catalytic residue at D500 (P = 5e-04);

MVP

0.83

MPC

0.010

ClinPred

0.86

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.32

gMVP

0.96

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