11-118407012-C-A

Variant names:

• chr11-118407012-C-A
• NM_006476.5:c.128C>A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_006476.5(ATP5MG):​c.128C>A​(p.Pro43His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: ATP5MG NM_006476.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.69

Genes affected

ATP5MG (HGNC:14247): (ATP synthase membrane subunit g) Mitochondrial ATP synthase catalyzes ATP synthesis, utilizing an electrochemical gradient of protons across the inner membrane during oxidative phosphorylation. It is composed of two linked multi-subunit complexes: the soluble catalytic core, F1, and the membrane-spanning component, Fo, which comprises the proton channel. The F1 complex consists of 5 different subunits (alpha, beta, gamma, delta, and epsilon) assembled in a ratio of 3 alpha, 3 beta, and a single representative of the other 3. The Fo seems to have nine subunits (a, b, c, d, e, f, g, F6 and 8). This gene encodes the g subunit of the Fo complex. Alternative splicing results in multiple transcript variants.[provided by RefSeq, Jun 2010]

ENSG00000285827 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.795

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP5MG	NM_006476.5	c.128C>A	p.Pro43His	missense_variant	Exon 2 of 3	ENST00000300688.8	NP_006467.4
ATP5MG	NR_033759.2	n.241C>A		non_coding_transcript_exon_variant	Exon 3 of 4
LOC100131626	NR_046369.1	n.231+10329G>T		intron_variant	Intron 3 of 3
LOC100131626	NR_046370.1	n.231+10329G>T		intron_variant	Intron 3 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP5MG	ENST00000300688.8	c.128C>A	p.Pro43His	missense_variant	Exon 2 of 3	1	NM_006476.5	ENSP00000300688.3
ENSG00000285827	ENST00000648261.1	c.-799+5295C>A		intron_variant	Intron 1 of 6			ENSP00000498126.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 15, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.128C>A (p.P43H) alteration is located in exon 2 (coding exon 2) of the ATP5L gene. This alteration results from a C to A substitution at nucleotide position 128, causing the proline (P) at amino acid position 43 to be replaced by a histidine (H). 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	0.89
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T;D;.
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D;D;D
M_CAP	Benign	0.064	D
MetaRNN	Pathogenic	0.79	D;D;D
MetaSVM	Uncertain	0.36	D
MutationAssessor	Pathogenic	3.2	M;.;.
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-6.8	D;D;.
REVEL	Uncertain	0.43
Sift	Uncertain	0.0020	D;D;.
Sift4G	Uncertain	0.0030	D;D;.
Polyphen		1.0	D;.;.
Vest4		0.79
MutPred		0.47		Loss of glycosylation at P43 (P = 0.0501);Loss of glycosylation at P43 (P = 0.0501);Loss of glycosylation at P43 (P = 0.0501);
MVP		0.67
MPC		0.62
ClinPred		0.99	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.75
gMVP		0.87

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.

Other links and lift over

hg19: chr11-118277727;