rs201929226

Positions:

• chr12-32708160-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM1 PP2 BS1_Supporting

The NM_001278464.2(DNM1L):​c.344C>T​(p.Thr115Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00024 in 1,597,708 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T115A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00024 (0 hom.)
• Consequence: DNM1L NM_001278464.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 2.79

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.

• PM1: In a domain Dynamin-type G (size 280) in uniprot entity DNM1L_HUMAN there are 17 pathogenic changes around while only 4 benign (81%) in NM_001278464.2
• 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.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000257 (39/152006) while in subpopulation NFE AF= 0.000515 (35/67986). AF 95% confidence interval is 0.000381. There are 0 homozygotes in gnomad4. There are 10 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNM1L	NM_001278464.2	c.344C>T	p.Thr115Met	missense_variant	5/21	ENST00000553257.6
DNM1L	NM_012062.5	c.305C>T	p.Thr102Met	missense_variant	4/20	ENST00000549701.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNM1L	ENST00000553257.6	c.344C>T	p.Thr115Met	missense_variant	5/21	2	NM_001278464.2
DNM1L	ENST00000549701.6	c.305C>T	p.Thr102Met	missense_variant	4/20	1	NM_012062.5

Frequencies

GnomAD3 genomes AF: 0.000257 AC: 39 AN: 151888 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000515

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000282 AC: 70 AN: 247996 Hom.: 0 AF XY: 0.000320 AC XY: 43 AN XY: 134472

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000292

Gnomad ASJ exome AF: 0.000200

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000200

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000409

Gnomad OTH exome AF: 0.000994

GnomAD4 exome AF: 0.000238 AC: 344 AN: 1445702 Hom.: 0 Cov.: 27 AF XY: 0.000271 AC XY: 195 AN XY: 720110

Gnomad4 AFR exome AF: 0.0000302

Gnomad4 AMR exome AF: 0.000360

Gnomad4 ASJ exome AF: 0.000463

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.000105

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000255

Gnomad4 OTH exome AF: 0.000317

GnomAD4 genome AF: 0.000257 AC: 39 AN: 152006 Hom.: 0 Cov.: 32 AF XY: 0.000135 AC XY: 10 AN XY: 74274

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.000289

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000515

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000307 Hom.: 0

Bravo AF: 0.000219

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000468 AC: 4

ExAC AF: 0.000289 AC: 35

EpiCase AF: 0.000710

EpiControl AF: 0.000831

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 20, 2022	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29110115, 34426522, 34356170) -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 17, 2024	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 102 of the DNM1L protein (p.Thr102Met). This variant is present in population databases (rs201929226, gnomAD 0.04%). This missense change has been observed in individual(s) with autosomal recessive encephalopathy (PMID: 29110115). This variant is also known as p.Thr115Met. ClinVar contains an entry for this variant (Variation ID: 214308). 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. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Dec 01, 2023

Variant summary: DNM1L c.305C>T (p.Thr102Met) results in a non-conservative amino acid change located in the Dynamin, GTPase domain (IPR001401) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00028 in 247996 control chromosomes (gnomAD). c.305C>T has been reported in the literature in an individual affected with developmental delay and neurological impairment (example: Hogarth_2018). This report does not provide unequivocal conclusions about association of the variant with Encephalopathy, Lethal, Due To Defective Mitochondrial Peroxisomal Fission 1, Autosomal Recessive. At least one publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (example: Hogarth_2018). The following publications have been ascertained in the context of this evaluation (PMID: 29110115, 34356170). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 07, 2023

The c.305C>T (p.T102M) alteration is located in exon 4 (coding exon 4) of the DNM1L gene. This alteration results from a C to T substitution at nucleotide position 305, causing the threonine (T) at amino acid position 102 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Optic atrophy 5;C3280660:Encephalopathy, lethal, due to defective mitochondrial peroxisomal fission 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	.;.;D;D;.;D;.;.;D
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.38	D
MetaRNN	Uncertain	0.74	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.8	M;.;M;.;M;.;M;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.80	D
PROVEAN	Uncertain	-3.6	D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.85
Sift	Benign	0.17	T;T;T;T;T;D;T;T;T
Sift4G	Benign	0.21	T;T;T;T;T;T;T;T;T
Polyphen		1.0	.;.;D;.;.;.;.;.;.
Vest4		0.40
MVP		0.99
MPC		2.2
ClinPred		0.54	D
GERP RS		4.9
Varity_R		0.43
gMVP		0.72

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: rs201929226; hg19: chr12-32861094;