Genetic Variant NM_018035.3:c.577G>A (chr19-41433291-C-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_018035.3(DMAC2):c.577G>A(p.Ala193Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000378 in 1,608,930 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00026 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00039 ( 0 hom. )

Consequence

DMAC2
NM_018035.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.49

Variant links:

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]

DMAC2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.34862763).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DMAC2	NM_018035.3 link	c.577G>A	p.Ala193Thr	missense_variant	Exon 5 of 6	ENST00000221943.14	NP_060505.2	Q9NW81-1A0A024R0K4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DMAC2	ENST00000221943.14 link	c.577G>A	p.Ala193Thr	missense_variant	Exon 5 of 6	2	NM_018035.3	ENSP00000221943.8		Q9NW81-1

Frequencies

GnomAD3 genomes

AF:

0.000263

AC:

AN:

152136

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000544

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000290

AC:

AN:

244540

Hom.:

AF XY:

0.000308

AC XY:

AN XY:

133142

show subpopulations

Gnomad AFR exome

AF:

0.0000641

Gnomad AMR exome

AF:

0.000378

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000329

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000486

Gnomad OTH exome

AF:

0.000333

GnomAD4 exome

AF:

0.000390

AC:

568

AN:

1456794

Hom.:

Cov.:

AF XY:

0.000389

AC XY:

282

AN XY:

724892

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000426

Gnomad4 ASJ exome

AF:

0.0000384

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000349

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000466

Gnomad4 OTH exome

AF:

0.000382

GnomAD4 genome

AF:

0.000263

AC:

AN:

152136

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74318

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000544

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000400

Hom.:

Bravo

AF:

0.000329

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000198

AC:

EpiCase

AF:

0.000600

EpiControl

AF:

0.000415

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 26, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.577G>A (p.A193T) alteration is located in exon 5 (coding exon 5) of the ATP5SL gene. This alteration results from a G to A substitution at nucleotide position 577, causing the alanine (A) at amino acid position 193 to be replaced by a threonine (T). 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

Uncertain

0.35

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.30

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.051

T;.;.;.;T;.

Eigen

Uncertain

0.60

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Uncertain

0.85

LIST_S2

Uncertain

0.87

D;D;D;D;D;D

M_CAP

Benign

0.065

MetaRNN

Benign

0.35

T;T;T;T;T;T

MetaSVM

Benign

-0.61

PrimateAI

Uncertain

0.52

PROVEAN

Uncertain

-2.9

D;.;D;.;.;.

REVEL

Benign

0.23

Sift

Uncertain

0.0050

D;.;D;.;.;.

Sift4G

Uncertain

0.011

D;D;D;D;D;.

Polyphen

1.0

D;.;.;D;.;.

Vest4

0.61

MVP

0.66

MPC

0.67

ClinPred

0.36

GERP RS

4.4

Varity_R

0.24

gMVP

0.36

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over