rs2272238

Variant names:

• chr12-32707368-G-A
• rs2272238
• NM_001278464.2:c.291G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_001278466.2(DNM1L):​c.86G>A​(p.Gly29Glu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.139 in 1,600,610 control chromosomes in the GnomAD database, including 16,194 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G29V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.15 (1899 hom., cov: 32)
  • Exomes 𝑓: 0.14 (14295 hom.)
• Consequence: DNM1L NM_001278466.2 missense, splice_region
• Scores: Splicing: ADA: 0.00001496
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.488
• Publications: 18 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: Benign. The variant received -19 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: 4.3944 (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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0012442768).
• BP6: Variant 12-32707368-G-A is Benign according to our data. Variant chr12-32707368-G-A is described in ClinVar as Benign. ClinVar VariationId is 260167.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.201 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001278466.2. 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.291G>A	p.Gly97Gly	splice_region synonymous	Exon 4 of 21	NP_001265393.1	O00429-6
	DNM1L	NM_012062.5	MANE Select	c.252G>A	p.Gly84Gly	splice_region synonymous	Exon 3 of 20	NP_036192.2	O00429-1
	DNM1L	NM_001278466.2		c.86G>A	p.Gly29Glu	missense splice_region	Exon 4 of 17	NP_001265395.1	O00429-7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNM1L	ENST00000553257.6	TSL:2 MANE Plus Clinical	c.291G>A	p.Gly97Gly	splice_region synonymous	Exon 4 of 21	ENSP00000449089.1	O00429-6
	DNM1L	ENST00000549701.6	TSL:1 MANE Select	c.252G>A	p.Gly84Gly	splice_region synonymous	Exon 3 of 20	ENSP00000450399.1	O00429-1
	DNM1L	ENST00000381000.8	TSL:1	c.291G>A	p.Gly97Gly	splice_region synonymous	Exon 4 of 20	ENSP00000370388.4	O00429-8

Frequencies

GnomAD3 genomes AF: 0.154 AC: 23369 AN: 151682 Hom.: 1890 Cov.: 32

Gnomad AFR AF: 0.205

Gnomad AMI AF: 0.274

Gnomad AMR AF: 0.129

Gnomad ASJ AF: 0.167

Gnomad EAS AF: 0.0741

Gnomad SAS AF: 0.126

Gnomad FIN AF: 0.0904

Gnomad MID AF: 0.210

Gnomad NFE AF: 0.144

Gnomad OTH AF: 0.166

GnomAD2 exomes AF: 0.127 AC: 31378 AN: 246126 AF XY: 0.130

Gnomad AFR exome AF: 0.202

Gnomad AMR exome AF: 0.0770

Gnomad ASJ exome AF: 0.174

Gnomad EAS exome AF: 0.0756

Gnomad FIN exome AF: 0.0974

Gnomad NFE exome AF: 0.142

Gnomad OTH exome AF: 0.137

GnomAD4 exome AF: 0.137 AC: 198650 AN: 1448810 Hom.: 14295 Cov.: 29 AF XY: 0.138 AC XY: 99136 AN XY: 720482

African (AFR) AF: 0.211 AC: 6947 AN: 32988

American (AMR) AF: 0.0839 AC: 3662 AN: 43640

Ashkenazi Jewish (ASJ) AF: 0.167 AC: 4322 AN: 25882

East Asian (EAS) AF: 0.0709 AC: 2783 AN: 39244

South Asian (SAS) AF: 0.128 AC: 10697 AN: 83804

European-Finnish (FIN) AF: 0.100 AC: 5325 AN: 53104

Middle Eastern (MID) AF: 0.191 AC: 1085 AN: 5686

European-Non Finnish (NFE) AF: 0.140 AC: 155129 AN: 1104618

Other (OTH) AF: 0.145 AC: 8700 AN: 59844

GnomAD4 genome AF: 0.154 AC: 23394 AN: 151800 Hom.: 1899 Cov.: 32 AF XY: 0.152 AC XY: 11243 AN XY: 74120

African (AFR) AF: 0.205 AC: 8479 AN: 41370

American (AMR) AF: 0.129 AC: 1967 AN: 15228

Ashkenazi Jewish (ASJ) AF: 0.167 AC: 579 AN: 3472

East Asian (EAS) AF: 0.0743 AC: 385 AN: 5182

South Asian (SAS) AF: 0.125 AC: 602 AN: 4806

European-Finnish (FIN) AF: 0.0904 AC: 946 AN: 10468

Middle Eastern (MID) AF: 0.212 AC: 62 AN: 292

European-Non Finnish (NFE) AF: 0.144 AC: 9765 AN: 67962

Other (OTH) AF: 0.170 AC: 359 AN: 2108

Alfa AF: 0.151 Hom.: 5053

Bravo AF: 0.159

TwinsUK AF: 0.139 AC: 516

ALSPAC AF: 0.138 AC: 532

ESP6500AA AF: 0.196 AC: 861

ESP6500EA AF: 0.146 AC: 1251

ExAC AF: 0.133 AC: 16103

Asia WGS AF: 0.136 AC: 471 AN: 3468

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Pathogenic	0.21
CADD	Benign	8.2
DANN	Uncertain	0.98
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.44	T
MetaRNN	Benign	0.0012	T
MetaSVM	Benign	-0.88	T
PhyloP100		-0.49
PROVEAN	Uncertain	-3.0	D
REVEL	Uncertain	0.35
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.22
ClinPred		0.031	T
GERP RS		-3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=69/31	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000015
dbscSNV1_RF	Benign	0.076
Splicevardb		2.0
SpliceAI score (max)		0.030		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: rs2272238; hg19: chr12-32860302; COSMIC: COSV56772870; COSMIC: COSV56772870;