rs879255688

Positions:

• chr12-32701418-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. 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).

• 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

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), DNM1L. . Gene score misZ 3.8282 (greater than the threshold 3.09). Trascript score misZ 5.2186 (greater than threshold 3.09). GenCC has associacion of gene with 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.
• 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 id is 253266.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1}. Variant chr12-32701418-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNM1L	NM_001278464.2	c.106A>G	p.Ser36Gly	missense_variant	2/21	ENST00000553257.6	NP_001265393.1
DNM1L	NM_012062.5	c.106A>G	p.Ser36Gly	missense_variant	2/20	ENST00000549701.6	NP_036192.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNM1L	ENST00000553257.6	c.106A>G	p.Ser36Gly	missense_variant	2/21	2	NM_001278464.2	ENSP00000449089
DNM1L	ENST00000549701.6	c.106A>G	p.Ser36Gly	missense_variant	2/20	1	NM_012062.5	ENSP00000450399

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 01, 2023	This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 36 of the DNM1L protein (p.Ser36Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal recessive encephalopathy (PMID: 27328748). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 253266). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 20, 2016	The S36G variant in the DNM1L gene has previously been reported in two siblings with slowly progressive infantile encephalopathy who were also compound heterozygous for a frameshift variant in DNM1L (Nasca et al., 2016). 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). The S36G variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations The S36G variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, we interpret S36G to be a pathogenic variant. -

Encephalopathy, lethal, due to defective mitochondrial peroxisomal fission 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 25, 2016

- -

Computational scores

Source: dbNSFP v4.3

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;D;.;D;.;.;.;D
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.95	D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.70	D
MetaRNN	Pathogenic	0.89	D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.2	H;H;H;.;H;.;.;H;H;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.79	T
PROVEAN	Uncertain	-3.1	D;D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0040	D;D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.015	D;D;D;D;D;D;D;D;D;D
Polyphen		0.53	.;.;P;.;.;.;.;.;.;.
Vest4		0.78
MutPred		0.61		Gain of catalytic residue at T33 (P = 4e-04);Gain of catalytic residue at T33 (P = 4e-04);Gain of catalytic residue at T33 (P = 4e-04);Gain of catalytic residue at T33 (P = 4e-04);Gain of catalytic residue at T33 (P = 4e-04);Gain of catalytic residue at T33 (P = 4e-04);Gain of catalytic residue at T33 (P = 4e-04);Gain of catalytic residue at T33 (P = 4e-04);Gain of catalytic residue at T33 (P = 4e-04);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

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

LitVar

Other links and lift over

dbSNP: rs879255688; hg19: chr12-32854352;