19-41433618-A-C

Variant names:

• chr19-41433618-A-C
• NM_018035.3:c.352T>G

Variant summary

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

The NM_018035.3(DMAC2):​c.352T>G​(p.Phe118Val) 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 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: DMAC2 NM_018035.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.260

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=0.07780495).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DMAC2	NM_018035.3	c.352T>G	p.Phe118Val	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.352T>G	p.Phe118Val	missense_variant	Exon 4 of 6	2	NM_018035.3	ENSP00000221943.8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461890 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727246

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: 0.00000360

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

Sep 25, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.352T>G (p.F118V) alteration is located in exon 4 (coding exon 4) of the ATP5SL gene. This alteration results from a T to G substitution at nucleotide position 352, causing the phenylalanine (F) at amino acid position 118 to be replaced by a valine (V). 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	0.24
BayesDel_addAF	Benign	-0.077	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	2.3
DANN	Benign	0.93
DEOGEN2	Benign	0.0082	.;T;.;.;.;.;.;.;T;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.084	N
LIST_S2	Benign	0.61	T;T;T;T;T;T;T;T;T;T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.078	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.97	T
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-2.2	N;N;.;D;.;N;.;.;.;.
REVEL	Benign	0.14
Sift	Benign	0.13	T;T;.;T;.;T;.;.;.;.
Sift4G	Uncertain	0.021	D;D;T;D;D;D;T;D;T;.
Polyphen		0.12	B;B;.;.;.;.;B;.;.;.
Vest4		0.41
MutPred		0.26		.;Loss of stability (P = 0.2276);.;.;Loss of stability (P = 0.2276);.;.;.;.;.;
MVP		0.56
MPC		0.23
ClinPred		0.13	T
GERP RS		-0.73
Varity_R		0.046
gMVP		0.60

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-41939523;