chr19-41432299-A-C

Variant names:

• chr19-41432299-A-C
• NM_018035.3:c.706T>G

Variant summary

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

The NM_018035.3(DMAC2):​c.706T>G​(p.Trp236Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,860 control chromosomes in the GnomAD database, with no homozygous occurrence. 12/20 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)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: DMAC2 NM_018035.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.24

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DMAC2	NM_018035.3	c.706T>G	p.Trp236Gly	missense_variant	Exon 6 of 6	ENST00000221943.14	NP_060505.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DMAC2	ENST00000221943.14	c.706T>G	p.Trp236Gly	missense_variant	Exon 6 of 6	2	NM_018035.3	ENSP00000221943.8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461860 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727236

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

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 16, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.706T>G (p.W236G) alteration is located in exon 6 (coding exon 6) of the ATP5SL gene. This alteration results from a T to G substitution at nucleotide position 706, causing the tryptophan (W) at amino acid position 236 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	0.13
BayesDel_addAF	Benign	-0.062	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	21
DANN	Benign	0.80
DEOGEN2	Benign	0.044	T;.;.
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.54	T;T;T
M_CAP	Benign	0.019	T
MetaRNN	Uncertain	0.72	D;D;D
MetaSVM	Benign	-1.0	T
PrimateAI	Benign	0.43	T
PROVEAN	Pathogenic	-5.9	D;.;D
REVEL	Benign	0.17
Sift	Uncertain	0.0010	D;.;D
Sift4G	Uncertain	0.022	D;D;D
Polyphen		0.82	P;.;.
Vest4		0.46
MutPred		0.65		Gain of disorder (P = 9e-04);.;.;
MVP		0.52
MPC		0.89
ClinPred		0.94	D
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.36
gMVP		0.54

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-41938204;