rs201929226

Variant names:

• chr12-32708160-C-T
• rs201929226
• NM_001278464.2:c.344C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 1P and 1B. PP2 BS1_Supporting

The NM_012062.5(DNM1L):​c.305C>T​(p.Thr102Met) 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. T102A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00024 (0 hom.)
• Consequence: DNM1L NM_012062.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:7
• Conservation: PhyloP100: 2.79
• Publications: 12 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
• encephalopathy, lethal, due to defective mitochondrial peroxisomal fission 1

  Inheritance: AD, AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• optic atrophy 5

  Inheritance: AD Classification: STRONG Submitted by: G2P
• 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: Uncertain_significance. The variant received 0 ACMG points.

• 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, optic atrophy 5, autosomal dominant optic atrophy, classic form, Leigh syndrome, encephalopathy due to mitochondrial and peroxisomal fission defect.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.344C>T	p.Thr115Met	missense	Exon 5 of 21	NP_001265393.1
	DNM1L	NM_012062.5	MANE Select	c.305C>T	p.Thr102Met	missense	Exon 4 of 20	NP_036192.2
	DNM1L	NM_001278465.2		c.344C>T	p.Thr115Met	missense	Exon 5 of 20	NP_001265394.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNM1L	ENST00000553257.6	TSL:2 MANE Plus Clinical	c.344C>T	p.Thr115Met	missense	Exon 5 of 21	ENSP00000449089.1
	DNM1L	ENST00000549701.6	TSL:1 MANE Select	c.305C>T	p.Thr102Met	missense	Exon 4 of 20	ENSP00000450399.1
	DNM1L	ENST00000381000.8	TSL:1	c.344C>T	p.Thr115Met	missense	Exon 5 of 20	ENSP00000370388.4

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

GnomAD2 exomes AF: 0.000282 AC: 70 AN: 247996 AF XY: 0.000320

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 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

African (AFR) AF: 0.0000302 AC: 1 AN: 33120

American (AMR) AF: 0.000360 AC: 16 AN: 44422

Ashkenazi Jewish (ASJ) AF: 0.000463 AC: 12 AN: 25902

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39480

South Asian (SAS) AF: 0.000105 AC: 9 AN: 85326

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53292

Middle Eastern (MID) AF: 0.00105 AC: 6 AN: 5712

European-Non Finnish (NFE) AF: 0.000255 AC: 280 AN: 1098598

Other (OTH) AF: 0.000317 AC: 19 AN: 59850

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

African (AFR) AF: 0.00 AC: 0 AN: 41458

American (AMR) AF: 0.0000655 AC: 1 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.000289 AC: 1 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10516

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000515 AC: 35 AN: 67986

Other (OTH) AF: 0.000474 AC: 1 AN: 2108

Alfa AF: 0.000300 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

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	4	-	not provided (4)
-	1	-	Inborn genetic diseases (1)
-	1	-	not specified (1)
-	1	-	Optic atrophy 5;C3280660:Encephalopathy, lethal, due to defective mitochondrial peroxisomal fission 1 (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.38	D
MetaRNN	Uncertain	0.74	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		2.8
PrimateAI	Pathogenic	0.80	D
PROVEAN	Uncertain	-3.6	D
REVEL	Pathogenic	0.85
Sift	Benign	0.17	T
Sift4G	Benign	0.21	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
Mutation Taster		=0/100	disease causing

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: rs201929226; hg19: chr12-32861094;