19-41433603-C-T

Variant names:

• chr19-41433603-C-T
• rs2039698634
• NM_018035.3:c.367G>A

Variant summary

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

The NM_018035.3(DMAC2):​c.367G>A​(p.Glu123Lys) 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. 13/20 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: DMAC2 NM_018035.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.425

Genes affected

DMAC2 (HGNC:25496): (distal membrane arm assembly component 2) Involved in mitochondrial respiratory chain complex I assembly. Colocalizes with mitochondrial respiratory chain complex I. [provided by Alliance of Genome Resources, Apr 2022]

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=0.098492116).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DMAC2	NM_018035.3	c.367G>A	p.Glu123Lys	missense_variant	Exon 4 of 6	ENST00000221943.14	NP_060505.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DMAC2	ENST00000221943.14	c.367G>A	p.Glu123Lys	missense_variant	Exon 4 of 6	2	NM_018035.3	ENSP00000221943.8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 10, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.367G>A (p.E123K) alteration is located in exon 4 (coding exon 4) of the ATP5SL gene. This alteration results from a G to A substitution at nucleotide position 367, causing the glutamic acid (E) at amino acid position 123 to be replaced by a lysine (K). 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	0.083
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	0.58
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0025	.;T;.;.;.;.;.;.;T;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.063	N
LIST_S2	Benign	0.66	T;T;T;T;T;T;T;T;T;T
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.098	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.90	T
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.73	N;N;.;N;.;N;.;.;.;.
REVEL	Benign	0.074
Sift	Benign	0.51	T;T;.;T;.;T;.;.;.;.
Sift4G	Benign	0.48	T;T;T;T;T;T;T;T;T;.
Polyphen		0.19	B;B;.;.;.;.;B;.;.;.
Vest4		0.32
MutPred		0.39		.;Gain of methylation at E123 (P = 0.0017);.;.;Gain of methylation at E123 (P = 0.0017);.;.;.;.;.;
MVP		0.53
MPC		0.19
ClinPred		0.093	T
GERP RS		-2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.037
gMVP		0.32

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: rs2039698634; hg19: chr19-41939508;