19-41433321-C-T

Variant names:

• chr19-41433321-C-T
• rs367830809
• NM_018035.3:c.547G>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.547G>A​(p.Gly183Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000235 in 1,611,470 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 0.00021 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00024 (0 hom.)
• Consequence: DMAC2 NM_018035.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.28

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=0.12565267).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DMAC2	NM_018035.3	c.547G>A	p.Gly183Ser	missense_variant	Exon 5 of 6	ENST00000221943.14	NP_060505.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DMAC2	ENST00000221943.14	c.547G>A	p.Gly183Ser	missense_variant	Exon 5 of 6	2	NM_018035.3	ENSP00000221943.8

Frequencies

GnomAD3 genomes AF: 0.000204 AC: 31 AN: 152160 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000323 AC: 80 AN: 247648 Hom.: 0 AF XY: 0.000335 AC XY: 45 AN XY: 134430

Gnomad AFR exome AF: 0.0000627

Gnomad AMR exome AF: 0.0000869

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000981

Gnomad FIN exome AF: 0.000864

Gnomad NFE exome AF: 0.000498

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000238 AC: 347 AN: 1459192 Hom.: 0 Cov.: 30 AF XY: 0.000271 AC XY: 197 AN XY: 726062

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000895

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000209

Gnomad4 FIN exome AF: 0.000566

Gnomad4 NFE exome AF: 0.000256

Gnomad4 OTH exome AF: 0.000182

GnomAD4 genome AF: 0.000210 AC: 32 AN: 152278 Hom.: 0 Cov.: 31 AF XY: 0.000215 AC XY: 16 AN XY: 74460

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.000565

Gnomad4 NFE AF: 0.000338

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000244 Hom.: 0

Bravo AF: 0.000162

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000362 AC: 44

EpiCase AF: 0.000327

EpiControl AF: 0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 26, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.547G>A (p.G183S) 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 547, causing the glycine (G) at amino acid position 183 to be replaced by a serine (S). 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	0.25
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.46
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.061	T;.;.;.;T;.
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.25	N
LIST_S2	Uncertain	0.89	D;D;D;D;D;D
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.13	T;T;T;T;T;T
MetaSVM	Benign	-0.75	T
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-3.1	D;.;D;.;.;.
REVEL	Benign	0.14
Sift	Benign	0.050	D;.;T;.;.;.
Sift4G	Uncertain	0.027	D;D;D;D;D;.
Polyphen		1.0	D;.;.;D;.;.
Vest4		0.50
MVP		0.69
MPC		0.69
ClinPred		0.061	T
GERP RS		3.4
Varity_R		0.092
gMVP		0.55

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs367830809; hg19: chr19-41939226;