NM_001278464.2:c.106A>G

Variant names:

• chr12-32701418-A-G
• rs879255688
• NM_001278464.2:c.106A>G

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PS3 PM1 PM2 PP2 PP3_Moderate PP5

The NM_001278464.2(DNM1L):​c.106A>G​(p.Ser36Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,706 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 Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV000330836: Introduction of the S36G variant into DNM1 deficient S. cerevisiae found that S36G is associated with reduced oxygen consumption, respiratory activity, and COX activity compared to wildtype (Nasca et al., 2016). Additional functional studies found that S36G is also associated with abnormal mitochondrial fission (Nasca et al., 2016).". Synonymous variant affecting the same amino acid position (i.e. S36S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: DNM1L NM_001278464.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 8.97
• Publications: 10 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: Pathogenic. The variant received 12 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000330836: Introduction of the S36G variant into DNM1 deficient S. cerevisiae found that S36G is associated with reduced oxygen consumption, respiratory activity, and COX activity compared to wildtype (Nasca et al., 2016). Additional functional studies found that S36G is also associated with abnormal mitochondrial fission (Nasca et al., 2016).
• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_001278464.2
• 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: 5.2186 (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, 0.889
• PP5: Variant 12-32701418-A-G is Pathogenic according to our data. Variant chr12-32701418-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 253266.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001278464.2. 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.106A>G	p.Ser36Gly	missense	Exon 2 of 21	NP_001265393.1	O00429-6
	DNM1L	NM_012062.5	MANE Select	c.106A>G	p.Ser36Gly	missense	Exon 2 of 20	NP_036192.2	O00429-1
	DNM1L	NM_001278465.2		c.106A>G	p.Ser36Gly	missense	Exon 2 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.106A>G	p.Ser36Gly	missense	Exon 2 of 21	ENSP00000449089.1	O00429-6
	DNM1L	ENST00000549701.6	TSL:1 MANE Select	c.106A>G	p.Ser36Gly	missense	Exon 2 of 20	ENSP00000450399.1	O00429-1
	DNM1L	ENST00000381000.8	TSL:1	c.106A>G	p.Ser36Gly	missense	Exon 2 of 20	ENSP00000370388.4	O00429-8

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461706 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727170

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111880

Other (OTH) AF: 0.00 AC: 0 AN: 60386

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	1	-	not provided (2)
1	-	-	Encephalopathy, lethal, due to defective mitochondrial peroxisomal fission 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.71
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.70	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.2	H
PhyloP100		9.0
PrimateAI	Uncertain	0.79	T
PROVEAN	Uncertain	-3.1	D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.015	D
Polyphen		0.53	P
Vest4		0.78
MutPred		0.61		Gain of catalytic residue at T33 (P = 4e-04)
MVP		0.98
MPC		2.1
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.70
gMVP		0.81
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: rs879255688; hg19: chr12-32854352;