rs148634653

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_001278464.2(DNM1L):c.2007C>T(p.Leu669Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0222 in 1,613,430 control chromosomes in the GnomAD database, including 517 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.018 ( 44 hom., cov: 33)

Exomes 𝑓: 0.023 ( 473 hom. )

Consequence

DNM1L
NM_001278464.2 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.150

Publications

5 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, Labcorp Genetics (formerly Invitae), G2P
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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.36).

BP6

Variant 12-32740492-C-T is Benign according to our data. Variant chr12-32740492-C-T is described in ClinVar as Benign. ClinVar VariationId is 137128.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.15 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0176 (2673/152262) while in subpopulation NFE AF = 0.0283 (1926/68016). AF 95% confidence interval is 0.0273. There are 44 homozygotes in GnomAd4. There are 1277 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 44 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNM1L	NM_001278464.2 link	c.2007C>T	p.Leu669Leu	synonymous_variant	Exon 19 of 21	ENST00000553257.6	NP_001265393.1
DNM1L	NM_012062.5 link	c.1968C>T	p.Leu656Leu	synonymous_variant	Exon 18 of 20	ENST00000549701.6	NP_036192.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNM1L	ENST00000553257.6 link	c.2007C>T	p.Leu669Leu	synonymous_variant	Exon 19 of 21	2	NM_001278464.2	ENSP00000449089.1
DNM1L	ENST00000549701.6 link	c.1968C>T	p.Leu656Leu	synonymous_variant	Exon 18 of 20	1	NM_012062.5	ENSP00000450399.1

Frequencies

GnomAD3 genomes

AF:

0.0176

AC:

2676

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00429

Gnomad AMI

AF:

0.0363

Gnomad AMR

AF:

0.0163

Gnomad ASJ

AF:

0.0343

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00705

Gnomad FIN

AF:

0.00821

Gnomad MID

AF:

0.0380

Gnomad NFE

AF:

0.0283

Gnomad OTH

AF:

0.0173

GnomAD2 exomes

AF:

0.0180

AC:

4515

AN:

250426

AF XY:

0.0187

show subpopulations

Gnomad AFR exome

AF:

0.00328

Gnomad AMR exome

AF:

0.0121

Gnomad ASJ exome

AF:

0.0350

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.0103

Gnomad NFE exome

AF:

0.0272

Gnomad OTH exome

AF:

0.0213

GnomAD4 exome

AF:

0.0227

AC:

33120

AN:

1461168

Hom.:

473

Cov.:

AF XY:

0.0225

AC XY:

16389

AN XY:

726870

show subpopulations

African (AFR)

AF:

0.00367

AC:

123

AN:

33472

American (AMR)

AF:

0.0133

AC:

593

AN:

44690

Ashkenazi Jewish (ASJ)

AF:

0.0338

AC:

883

AN:

26116

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39684

South Asian (SAS)

AF:

0.00953

AC:

821

AN:

86164

European-Finnish (FIN)

AF:

0.0103

AC:

547

AN:

53364

Middle Eastern (MID)

AF:

0.0338

AC:

195

AN:

5766

European-Non Finnish (NFE)

AF:

0.0258

AC:

28630

AN:

1111560

Other (OTH)

AF:

0.0220

AC:

1325

AN:

60352

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

1570

3140

4709

6279

7849

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1016

2032

3048

4064

5080

<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:

0.0176

AC:

2673

AN:

152262

Hom.:

Cov.:

AF XY:

0.0172

AC XY:

1277

AN XY:

74438

show subpopulations

African (AFR)

AF:

0.00428

AC:

178

AN:

41566

American (AMR)

AF:

0.0163

AC:

249

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.0343

AC:

119

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5186

South Asian (SAS)

AF:

0.00705

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00821

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.0374

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0283

AC:

1926

AN:

68016

Other (OTH)

AF:

0.0166

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

138

276

413

551

689

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

102

136

170

<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:

0.0230

Hom.:

Bravo

AF:

0.0175

Asia WGS

AF:

0.00491

AC:

AN:

3478

EpiCase

AF:

0.0299

EpiControl

AF:

0.0315

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jan 04, 2017

Mayo Clinic Laboratories, Mayo Clinic

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jun 12, 2012

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.36

CADD

Benign

6.7

(source)

DANN

Benign

0.90

PhyloP100

0.15

Mutation Taster

=97/3

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over