12-32722472-A-G

Variant names:

• chr12-32722472-A-G
• rs10844318
• NM_001278464.2:c.957A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001278464.2(DNM1L):​c.957A>G​(p.Thr319Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.135 in 1,612,406 control chromosomes in the GnomAD database, including 15,139 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1555 hom., cov: 32)
  • Exomes 𝑓: 0.13 (13584 hom.)
• Consequence: DNM1L NM_001278464.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.749
• Publications: 11 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 12-32722472-A-G is Benign according to our data. Variant chr12-32722472-A-G is described in ClinVar as Benign. ClinVar VariationId is 260168.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.749 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.166 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNM1L	NM_001278464.2	MANE Plus Clinical	c.957A>G	p.Thr319Thr	synonymous	Exon 10 of 21	NP_001265393.1
	DNM1L	NM_012062.5	MANE Select	c.918A>G	p.Thr306Thr	synonymous	Exon 9 of 20	NP_036192.2
	DNM1L	NM_001278465.2		c.957A>G	p.Thr319Thr	synonymous	Exon 10 of 20	NP_001265394.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNM1L	ENST00000553257.6	TSL:2 MANE Plus Clinical	c.957A>G	p.Thr319Thr	synonymous	Exon 10 of 21	ENSP00000449089.1
	DNM1L	ENST00000549701.6	TSL:1 MANE Select	c.918A>G	p.Thr306Thr	synonymous	Exon 9 of 20	ENSP00000450399.1
	DNM1L	ENST00000381000.8	TSL:1	c.957A>G	p.Thr319Thr	synonymous	Exon 10 of 20	ENSP00000370388.4

Frequencies

GnomAD3 genomes AF: 0.141 AC: 21495 AN: 152092 Hom.: 1551 Cov.: 32

Gnomad AFR AF: 0.169

Gnomad AMI AF: 0.273

Gnomad AMR AF: 0.122

Gnomad ASJ AF: 0.161

Gnomad EAS AF: 0.0735

Gnomad SAS AF: 0.105

Gnomad FIN AF: 0.0892

Gnomad MID AF: 0.187

Gnomad NFE AF: 0.141

Gnomad OTH AF: 0.152

GnomAD2 exomes AF: 0.123 AC: 30841 AN: 250954 AF XY: 0.125

Gnomad AFR exome AF: 0.171

Gnomad AMR exome AF: 0.0779

Gnomad ASJ exome AF: 0.168

Gnomad EAS exome AF: 0.0769

Gnomad FIN exome AF: 0.0970

Gnomad NFE exome AF: 0.141

Gnomad OTH exome AF: 0.135

GnomAD4 exome AF: 0.134 AC: 195843 AN: 1460196 Hom.: 13584 Cov.: 32 AF XY: 0.134 AC XY: 97565 AN XY: 726412

African (AFR) AF: 0.175 AC: 5856 AN: 33430

American (AMR) AF: 0.0838 AC: 3747 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.162 AC: 4242 AN: 26124

East Asian (EAS) AF: 0.0708 AC: 2808 AN: 39648

South Asian (SAS) AF: 0.112 AC: 9646 AN: 86208

European-Finnish (FIN) AF: 0.100 AC: 5339 AN: 53366

Middle Eastern (MID) AF: 0.176 AC: 888 AN: 5044

European-Non Finnish (NFE) AF: 0.139 AC: 154925 AN: 1111382

Other (OTH) AF: 0.139 AC: 8392 AN: 60272

GnomAD4 genome AF: 0.141 AC: 21500 AN: 152210 Hom.: 1555 Cov.: 32 AF XY: 0.139 AC XY: 10335 AN XY: 74438

African (AFR) AF: 0.169 AC: 7017 AN: 41520

American (AMR) AF: 0.122 AC: 1866 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.161 AC: 557 AN: 3468

East Asian (EAS) AF: 0.0737 AC: 382 AN: 5184

South Asian (SAS) AF: 0.104 AC: 503 AN: 4820

European-Finnish (FIN) AF: 0.0892 AC: 945 AN: 10594

Middle Eastern (MID) AF: 0.187 AC: 55 AN: 294

European-Non Finnish (NFE) AF: 0.141 AC: 9610 AN: 68016

Other (OTH) AF: 0.150 AC: 317 AN: 2112

Alfa AF: 0.140 Hom.: 1468

Bravo AF: 0.146

Asia WGS AF: 0.105 AC: 366 AN: 3476

EpiCase AF: 0.149

EpiControl AF: 0.154

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 22, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Optic atrophy 5 Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	6.6
DANN	Benign	0.73
PhyloP100		-0.75
Mutation Taster		=97/3	polymorphism (auto)

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: rs10844318; hg19: chr12-32875406; COSMIC: COSV56772893; COSMIC: COSV56772893;