rs1555229948

Variant names:

• chr12-32679368-A-C
• rs1555229948
• NM_001278464.2:c.5A>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP2 PP3_Moderate PP5

The NM_012062.5(DNM1L):​c.5A>C​(p.Glu2Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,424 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: DNM1L NM_012062.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.73
• Publications: 4 publications found

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]

DNM1L Gene-Disease associations (from GenCC):

• encephalopathy due to mitochondrial and peroxisomal fission defect

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• optic atrophy 5

  Inheritance: AD Classification: STRONG Submitted by: G2P
• encephalopathy, lethal, due to defective mitochondrial peroxisomal fission 1

  Inheritance: AR, AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Orphanet
• autosomal dominant optic atrophy, classic form

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Leigh syndrome

  Inheritance: AR, AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 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 optic atrophy 5, encephalopathy, lethal, due to defective mitochondrial peroxisomal fission 1, encephalopathy due to mitochondrial and peroxisomal fission defect, Leigh syndrome, autosomal dominant optic atrophy, classic form.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.894
• PP5: Variant 12-32679368-A-C is Pathogenic according to our data. Variant chr12-32679368-A-C is described in ClinVar as Pathogenic. ClinVar VariationId is 446169.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012062.5. 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
	DNM1L	NM_001278464.2	MANE Plus Clinical	c.5A>C	p.Glu2Ala	missense	Exon 1 of 21	NP_001265393.1	O00429-6
	DNM1L	NM_012062.5	MANE Select	c.5A>C	p.Glu2Ala	missense	Exon 1 of 20	NP_036192.2	O00429-1
	DNM1L	NM_001278465.2		c.5A>C	p.Glu2Ala	missense	Exon 1 of 20	NP_001265394.1	O00429-8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNM1L	ENST00000553257.6	TSL:2 MANE Plus Clinical	c.5A>C	p.Glu2Ala	missense	Exon 1 of 21	ENSP00000449089.1	O00429-6
	DNM1L	ENST00000549701.6	TSL:1 MANE Select	c.5A>C	p.Glu2Ala	missense	Exon 1 of 20	ENSP00000450399.1	O00429-1
	DNM1L	ENST00000381000.8	TSL:1	c.5A>C	p.Glu2Ala	missense	Exon 1 of 20	ENSP00000370388.4	O00429-8

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460424 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726670

African (AFR) AF: 0.00 AC: 0 AN: 33448

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

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26102

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86182

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53204

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111016

Other (OTH) AF: 0.00 AC: 0 AN: 60324

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Optic atrophy 5 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.83	D
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		8.7
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-5.2	D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0060	D
Polyphen		0.99	D
Vest4		0.73
MutPred		0.45		Gain of catalytic residue at I5 (P = 0)
MVP		0.96
MPC		1.2
ClinPred		1.0	D
GERP RS		4.7
PromoterAI		0.34	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.79
gMVP		0.72
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1555229948; hg19: chr12-32832302;