11-118401703-C-T

Variant names:

• chr11-118401703-C-T
• rs1948928140
• ENST00000648261:c.-813C>T

Variant summary

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

The ENST00000648261(ENSG00000285827):​c.-813C>T variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.000000684 in 1,461,212 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ENSG00000285827 ENST00000648261 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.00

Genes affected

ENSG00000285827 (HGNC:):

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]

ACMG classification

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
ATP5MG	NM_006476.5	c.38C>T	p.Pro13Leu	missense_variant	Exon 1 of 3	ENST00000300688.8	NP_006467.4
ATP5MG	NR_033759.2	n.98C>T		non_coding_transcript_exon_variant	Exon 1 of 4
LOC100131626	NR_046369.1	n.231+15638G>A		intron_variant	Intron 3 of 3
LOC100131626	NR_046370.1	n.231+15638G>A		intron_variant	Intron 3 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENSG00000285827	ENST00000648261	c.-813C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 7			ENSP00000498126.1
ATP5MG	ENST00000300688.8	c.38C>T	p.Pro13Leu	missense_variant	Exon 1 of 3	1	NM_006476.5	ENSP00000300688.3
ENSG00000285827	ENST00000648261	c.-813C>T		5_prime_UTR_variant	Exon 1 of 7			ENSP00000498126.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461212 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726870

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 27, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.38C>T (p.P13L) alteration is located in exon 1 (coding exon 1) of the ATP5L gene. This alteration results from a C to T substitution at nucleotide position 38, causing the proline (P) at amino acid position 13 to be replaced by a leucine (L). 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	Uncertain	0.061	T
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	24
DANN	Benign	0.93
DEOGEN2	Benign	0.29	T;.;T;.
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.14
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.69	T;T;T;T
M_CAP	Benign	0.014	T
MetaRNN	Uncertain	0.44	T;T;T;T
MetaSVM	Benign	-0.83	T
MutationAssessor	Uncertain	2.1	M;.;.;.
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-3.9	D;.;D;.
REVEL	Benign	0.24
Sift	Benign	0.18	T;.;T;.
Sift4G	Benign	0.16	T;.;T;.
Polyphen		0.015	B;.;.;.
Vest4		0.54
MutPred		0.55		Gain of helix (P = 0.027);Gain of helix (P = 0.027);Gain of helix (P = 0.027);Gain of helix (P = 0.027);
MVP		0.18
MPC		0.13
ClinPred		0.88	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.25
gMVP		0.79

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

Publications

LitVar

Other links and lift over

dbSNP: rs1948928140; hg19: chr11-118272418;