14-50322534-A-G

Position:

• chr14-50322534-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001382507.1(DMAC2L):​c.131A>G​(p.Asp44Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DMAC2L NM_001382507.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.29

Genes affected

DMAC2L (HGNC:18799): (distal membrane arm assembly component 2 like) 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. This gene encodes the subunit s, also known as factor B, of the proton channel. This subunit is necessary for the energy transduction activity of the ATP synthase complexes. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

DMAC2L (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16673428).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DMAC2L	NM_001382507.1	c.131A>G	p.Asp44Gly	missense_variant	4/6	ENST00000557421.7	NP_001369436.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DMAC2L	ENST00000557421.7	c.131A>G	p.Asp44Gly	missense_variant	4/6	5	NM_001382507.1	ENSP00000506374.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 28, 2023

The c.176A>G (p.D59G) alteration is located in exon 3 (coding exon 3) of the ATP5S gene. This alteration results from a A to G substitution at nucleotide position 176, causing the aspartic acid (D) at amino acid position 59 to be replaced by a glycine (G). 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	0.21
BayesDel_addAF	Benign	-0.0075	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	21
DANN	Uncertain	0.99
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.21
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Uncertain	0.96	D;D;D;D;D
M_CAP	Benign	0.068	D
MetaRNN	Benign	0.17	T;T;T;T;T
MetaSVM	Uncertain	-0.024	T
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-2.4	N;N;N;N;.
REVEL	Benign	0.26
Sift	Benign	0.098	T;T;T;T;.
Sift4G	Benign	0.32	T;T;T;T;.
Vest4		0.52
MutPred		0.28		.;.;.;Gain of MoRF binding (P = 0.0564);.;
MVP		0.90
MPC		0.30
ClinPred		0.48	T
GERP RS		0.47
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.34

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

LitVar

Other links and lift over

dbSNP: rs1421111735; hg19: chr14-50789252;