19-41433431-C-A

Variant names:

• chr19-41433431-C-A
• rs781938587
• NM_018035.3:c.437G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_018035.3(DMAC2):​c.437G>T​(p.Arg146Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,460,986 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R146G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (1 hom.)
• Consequence: DMAC2 NM_018035.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.553
• Publications: 2 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.096675694).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018035.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DMAC2	NM_018035.3	MANE Select	c.437G>T	p.Arg146Leu	missense	Exon 5 of 6	NP_060505.2	Q9NW81-1
	DMAC2	NM_001167867.2		c.455G>T	p.Arg152Leu	missense	Exon 5 of 6	NP_001161339.1	Q9NW81-4
	DMAC2	NM_001320840.2		c.374G>T	p.Arg125Leu	missense	Exon 4 of 5	NP_001307769.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DMAC2	ENST00000221943.14	TSL:2 MANE Select	c.437G>T	p.Arg146Leu	missense	Exon 5 of 6	ENSP00000221943.8	Q9NW81-1
	DMAC2	ENST00000438807.7	TSL:1	c.352+106G>T		intron	N/A	ENSP00000397413.3	Q9NW81-2
	DMAC2	ENST00000417807.7	TSL:2	c.455G>T	p.Arg152Leu	missense	Exon 5 of 6	ENSP00000403910.2	Q9NW81-4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250470 AF XY: 0.00000738

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1460986 Hom.: 1 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 726706

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26092

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86184

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53258

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5760

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111458

Other (OTH) AF: 0.00 AC: 0 AN: 60362

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	5.0
DANN	Benign	0.85
DEOGEN2	Benign	0.0044	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.092	T
M_CAP	Benign	0.0050	T
MetaRNN	Benign	0.097	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.55
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.92	N
REVEL	Benign	0.057
Sift	Benign	0.70	T
Sift4G	Benign	0.69	T
Polyphen		0.0	B
Vest4		0.18
MutPred		0.34		Loss of ubiquitination at K148 (P = 0.0661)
MVP		0.19
MPC		0.21
ClinPred		0.040	T
GERP RS		-1.3
Varity_R		0.033
gMVP		0.31
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs781938587; hg19: chr19-41939336;