rs79393011

chr12-32733738-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001278464.2(DNM1L):c.1509A>G(p.Glu503=) 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_001278464.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.26

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]

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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 male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 6 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNM1L	NM_001278464.2	c.1509A>G	p.Glu503=	synonymous_variant	14/21	ENST00000553257.6
DNM1L	NM_012062.5	c.1470A>G	p.Glu490=	synonymous_variant	13/20	ENST00000549701.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNM1L	ENST00000553257.6	c.1509A>G	p.Glu503=	synonymous_variant	14/21	2	NM_001278464.2
DNM1L	ENST00000549701.6	c.1470A>G	p.Glu490=	synonymous_variant	13/20	1	NM_012062.5

Frequencies

GnomAD3 genomes AF: 0.00804 AC: 1224 AN: 152212 Hom.: 6 Cov.: 33

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

GnomAD3 exomes AF: 0.00779 AC: 1959 AN: 251334 Hom.: 11 AF XY: 0.00819 AC XY: 1113 AN XY: 135832

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 SAS exome AF: 0.00317

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.: 84 Cov.: 30 AF XY: 0.0103 AC XY: 7486 AN XY: 727112

Gnomad4 AFR exome AF: 0.00218

Gnomad4 AMR exome AF: 0.00778

Gnomad4 ASJ exome AF: 0.00815

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00322

Gnomad4 FIN exome AF: 0.00730

Gnomad4 NFE exome AF: 0.0119

Gnomad4 OTH exome AF: 0.0114

GnomAD4 genome AF: 0.00802 AC: 1222 AN: 152330 Hom.: 6 Cov.: 33 AF XY: 0.00760 AC XY: 566 AN XY: 74492

Gnomad4 AFR AF: 0.00277

Gnomad4 AMR AF: 0.00876

Gnomad4 ASJ AF: 0.00864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.00622

Gnomad4 NFE AF: 0.0122

Gnomad4 OTH AF: 0.0128

Alfa AF: 0.0104 Hom.: 5

Bravo AF: 0.00812

Asia WGS AF: 0.00115 AC: 4 AN: 3476

EpiCase AF: 0.0145

EpiControl AF: 0.0141

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 03, 2023	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	DNM1L: BP4, BP7, BS1, BS2 -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Aug 07, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 17, 2013	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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
Cadd	Benign	5.6
Dann	Benign	0.86
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

LitVar

Other links and lift over

dbSNP: rs79393011; hg19: chr12-32886672;