Genetic Variant DNM1L:p.Glu503Glu (chr12-32733738-A-G) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_012062.5(DNM1L):c.1470A>G(p.Glu490Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0102 in 1,613,920 control chromosomes in the GnomAD database, including 90 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0080 ( 6 hom., cov: 33)

Exomes 𝑓: 0.010 ( 84 hom. )

Consequence

DNM1L
NM_012062.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 1.26

Publications

3 publications found

Variant links:

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 links:

YARS2 (HGNC:24249): (tyrosyl-tRNA synthetase 2) This gene encodes a mitochondrial protein that catalyzes the attachment of tyrosine to tRNA(Tyr). Mutations in this gene are associated with myopathy with lactic acidosis and sideroblastic anemia type 2 (MLASA2). [provided by RefSeq, Jan 2011]

YARS2 Gene-Disease associations (from GenCC):

myopathy, lactic acidosis, and sideroblastic anemia 2
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
myopathy, lactic acidosis, and sideroblastic anemia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

YARS2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.51).

BP6

Variant 12-32733738-A-G is Benign according to our data. Variant chr12-32733738-A-G is described in ClinVar as Benign. ClinVar VariationId is 137127.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.26 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00802 (1222/152330) while in subpopulation NFE AF = 0.0122 (830/68030). AF 95% confidence interval is 0.0115. There are 6 homozygotes in GnomAd4. There are 566 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 6 AD,AR gene

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DNM1L	NM_001278464.2	MANE Plus Clinical	c.1509A>G	p.Glu503Glu	synonymous	Exon 14 of 21	NP_001265393.1	O00429-6
DNM1L	NM_012062.5	MANE Select	c.1470A>G	p.Glu490Glu	synonymous	Exon 13 of 20	NP_036192.2	O00429-1
DNM1L	NM_001278465.2		c.1509A>G	p.Glu503Glu	synonymous	Exon 14 of 20	NP_001265394.1	O00429-8

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DNM1L	ENST00000553257.6	TSL:2 MANE Plus Clinical	c.1509A>G	p.Glu503Glu	synonymous	Exon 14 of 21	ENSP00000449089.1	O00429-6
DNM1L	ENST00000549701.6	TSL:1 MANE Select	c.1470A>G	p.Glu490Glu	synonymous	Exon 13 of 20	ENSP00000450399.1	O00429-1
DNM1L	ENST00000381000.8	TSL:1	c.1509A>G	p.Glu503Glu	synonymous	Exon 14 of 20	ENSP00000370388.4	O00429-8

Frequencies

GnomAD3 genomes

AF:

0.00804

AC:

1224

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00277

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.00877

Gnomad ASJ

AF:

0.00864

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00227

Gnomad FIN

AF:

0.00622

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.0122

Gnomad OTH

AF:

0.0129

GnomAD2 exomes

AF:

0.00779

AC:

1959

AN:

251334

AF XY:

0.00819

show subpopulations

Gnomad AFR exome

AF:

0.00197

Gnomad AMR exome

AF:

0.00717

Gnomad ASJ exome

AF:

0.00873

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00628

Gnomad NFE exome

AF:

0.0114

Gnomad OTH exome

AF:

0.00995

GnomAD4 exome

AF:

0.0104

AC:

15271

AN:

1461590

Hom.:

Cov.:

AF XY:

0.0103

AC XY:

7486

AN XY:

727112

show subpopulations

African (AFR)

AF:

0.00218

AC:

AN:

33470

American (AMR)

AF:

0.00778

AC:

348

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00815

AC:

213

AN:

26124

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39632

South Asian (SAS)

AF:

0.00322

AC:

278

AN:

86250

European-Finnish (FIN)

AF:

0.00730

AC:

390

AN:

53408

Middle Eastern (MID)

AF:

0.00868

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.0119

AC:

13232

AN:

1111848

Other (OTH)

AF:

0.0114

AC:

686

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

Heterozygous variant carriers

758

1517

2275

3034

3792

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

484

968

1452

1936

2420

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00802

AC:

1222

AN:

152330

Hom.:

Cov.:

AF XY:

0.00760

AC XY:

566

AN XY:

74492

show subpopulations

African (AFR)

AF:

0.00277

AC:

115

AN:

41576

American (AMR)

AF:

0.00876

AC:

134

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00864

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00228

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00622

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0122

AC:

830

AN:

68030

Other (OTH)

AF:

0.0128

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

128

191

255

319

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0104

Hom.:

Bravo

AF:

0.00812

Asia WGS

AF:

0.00115

AC:

AN:

3476

EpiCase

AF:

0.0145

EpiControl

AF:

0.0141

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

not specified (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.51

CADD

Benign

5.6

(source)

DANN

Benign

0.86

PhyloP100

1.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=99/1

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over