NM_001278464.2:c.57C>T

Variant names:

• chr12-32679420-C-T
• rs1302943262
• NM_001278464.2:c.57C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP6_Moderate

The NM_001278464.2(DNM1L):​c.57C>T​(p.Gly19Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,613,632 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: DNM1L NM_001278464.2 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.274
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 12-32679420-C-T is Benign according to our data. Variant chr12-32679420-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1653376.Status of the report is criteria_provided_single_submitter, 1 stars.

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.57C>T	p.Gly19Gly	synonymous	Exon 1 of 21	NP_001265393.1	O00429-6
	DNM1L	NM_012062.5	MANE Select	c.57C>T	p.Gly19Gly	synonymous	Exon 1 of 20	NP_036192.2	O00429-1
	DNM1L	NM_001278465.2		c.57C>T	p.Gly19Gly	synonymous	Exon 1 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.57C>T	p.Gly19Gly	synonymous	Exon 1 of 21	ENSP00000449089.1	O00429-6
	DNM1L	ENST00000549701.6	TSL:1 MANE Select	c.57C>T	p.Gly19Gly	synonymous	Exon 1 of 20	ENSP00000450399.1	O00429-1
	DNM1L	ENST00000381000.8	TSL:1	c.57C>T	p.Gly19Gly	synonymous	Exon 1 of 20	ENSP00000370388.4	O00429-8

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152230 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00 AC: 0 AN: 250490 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461284 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726988

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53010

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111874

Other (OTH) AF: 0.00 AC: 0 AN: 60374

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152348 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74506

African (AFR) AF: 0.00 AC: 0 AN: 41586

American (AMR) AF: 0.00 AC: 0 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.27
CADD	Benign	20
DANN	Benign	0.94
PhyloP100		-0.27
PromoterAI		0.079	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.36		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.36		Position offset: -6

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1302943262; hg19: chr12-32832354;