rs148634653

Positions:

• chr12-32740492-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001278464.2(DNM1L):​c.2007C>T​(p.Leu669=) 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.150

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 -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 id 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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 44 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNM1L	NM_001278464.2	c.2007C>T	p.Leu669=	synonymous_variant	19/21	ENST00000553257.6
DNM1L	NM_012062.5	c.1968C>T	p.Leu656=	synonymous_variant	18/20	ENST00000549701.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNM1L	ENST00000553257.6	c.2007C>T	p.Leu669=	synonymous_variant	19/21	2	NM_001278464.2
DNM1L	ENST00000549701.6	c.1968C>T	p.Leu656=	synonymous_variant	18/20	1	NM_012062.5

Frequencies

GnomAD3 genomes AF: 0.0176 AC: 2676 AN: 152144 Hom.: 44 Cov.: 33

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

GnomAD3 exomes AF: 0.0180 AC: 4515 AN: 250426 Hom.: 62 AF XY: 0.0187 AC XY: 2536 AN XY: 135350

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 SAS exome AF: 0.00873

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.: 30 AF XY: 0.0225 AC XY: 16389 AN XY: 726870

Gnomad4 AFR exome AF: 0.00367

Gnomad4 AMR exome AF: 0.0133

Gnomad4 ASJ exome AF: 0.0338

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00953

Gnomad4 FIN exome AF: 0.0103

Gnomad4 NFE exome AF: 0.0258

Gnomad4 OTH exome AF: 0.0220

GnomAD4 genome AF: 0.0176 AC: 2673 AN: 152262 Hom.: 44 Cov.: 33 AF XY: 0.0172 AC XY: 1277 AN XY: 74438

Gnomad4 AFR AF: 0.00428

Gnomad4 AMR AF: 0.0163

Gnomad4 ASJ AF: 0.0343

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00705

Gnomad4 FIN AF: 0.00821

Gnomad4 NFE AF: 0.0283

Gnomad4 OTH AF: 0.0166

Alfa AF: 0.0230 Hom.: 29

Bravo AF: 0.0175

Asia WGS AF: 0.00491 AC: 17 AN: 3478

EpiCase AF: 0.0299

EpiControl AF: 0.0315

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 12, 2012	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. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jan 04, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	6.7
DANN	Benign	0.90

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

LitVar

Other links and lift over

dbSNP: rs148634653; hg19: chr12-32893426;