12-32679385-A-G

Variant names:

• chr12-32679385-A-G
• NM_001278464.2:c.22A>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_012062.5(DNM1L):​c.22A>G​(p.Ile8Val) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,496 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: DNM1L NM_012062.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.77

Genes affected

DNM1L (HGNC:2973): (dynamin 1 like) This gene encodes a member of the dynamin superfamily of GTPases. The encoded protein mediates mitochondrial and peroxisomal division, and is involved in developmentally regulated apoptosis and programmed necrosis. Dysfunction of this gene is implicated in several neurological disorders, including Alzheimer's disease. Mutations in this gene are associated with the autosomal dominant disorder, encephalopathy, lethal, due to defective mitochondrial and peroxisomal fission (EMPF). Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jun 2013]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the DNM1L gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 31 curated pathogenic missense variants (we use a threshold of 10). The gene has 9 curated benign missense variants. Gene score misZ: 3.8282 (above the threshold of 3.09). Trascript score misZ: 5.3198 (above the threshold of 3.09). GenCC associations: The gene is linked to encephalopathy, lethal, due to defective mitochondrial peroxisomal fission 1, encephalopathy due to mitochondrial and peroxisomal fission defect, optic atrophy 5, Leigh syndrome, autosomal dominant optic atrophy, classic form.
• BP4: Computational evidence support a benign effect (MetaRNN=0.35011822).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNM1L	NM_001278464.2	c.22A>G	p.Ile8Val	missense_variant	Exon 1 of 21	ENST00000553257.6	NP_001265393.1
DNM1L	NM_012062.5	c.22A>G	p.Ile8Val	missense_variant	Exon 1 of 20	ENST00000549701.6	NP_036192.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNM1L	ENST00000553257.6	c.22A>G	p.Ile8Val	missense_variant	Exon 1 of 21	2	NM_001278464.2	ENSP00000449089.1
DNM1L	ENST00000549701.6	c.22A>G	p.Ile8Val	missense_variant	Exon 1 of 20	1	NM_012062.5	ENSP00000450399.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461496 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727082

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.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	22
DANN	Benign	0.91
DEOGEN2	Benign	0.31	.;.;T;T;.;T;.;.;.;T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.095
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.89	D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.30	D
MetaRNN	Benign	0.35	T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.0077	T
MutationAssessor	Benign	0.47	N;N;N;.;N;.;.;N;N;.
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-0.56	N;N;N;N;N;N;N;N;N;N
REVEL	Uncertain	0.41
Sift	Benign	1.0	T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	1.0	T;T;T;T;T;T;T;T;T;T
Polyphen		0.019	.;.;B;.;.;.;.;.;.;.
Vest4		0.36
MutPred		0.50		Gain of catalytic residue at I5 (P = 6e-04);Gain of catalytic residue at I5 (P = 6e-04);Gain of catalytic residue at I5 (P = 6e-04);Gain of catalytic residue at I5 (P = 6e-04);Gain of catalytic residue at I5 (P = 6e-04);Gain of catalytic residue at I5 (P = 6e-04);Gain of catalytic residue at I5 (P = 6e-04);Gain of catalytic residue at I5 (P = 6e-04);Gain of catalytic residue at I5 (P = 6e-04);Gain of catalytic residue at I5 (P = 6e-04);
MVP		0.83
MPC		0.92
ClinPred		0.42	T
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.34
gMVP		0.43

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: chr12-32832319;