12-32731084-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM1 PM2 PP2 BP4

The NM_001278464.2(DNM1L):c.1189C>T(p.Leu397Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,613,868 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: DNM1L NM_001278464.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.932

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 Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a region_of_interest Middle domain (size 145) in uniprot entity DNM1L_HUMAN there are 27 pathogenic changes around while only 1 benign (96%) in NM_001278464.2
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, DNM1L
• BP4: Computational evidence support a benign effect (MetaRNN=0.3377189).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNM1L	NM_001278464.2	c.1189C>T	p.Leu397Phe	missense_variant	11/21	ENST00000553257.6
DNM1L	NM_012062.5	c.1150C>T	p.Leu384Phe	missense_variant	10/20	ENST00000549701.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNM1L	ENST00000553257.6	c.1189C>T	p.Leu397Phe	missense_variant	11/21	2	NM_001278464.2
DNM1L	ENST00000549701.6	c.1150C>T	p.Leu384Phe	missense_variant	10/20	1	NM_012062.5

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152102 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461766 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727188

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152102 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74312

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000478

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 10, 2023

This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 384 of the DNM1L protein (p.Leu384Phe). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with DNM1L-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
Cadd	Benign	23
Dann	Uncertain	1.0
Eigen	Benign	0.083
Eigen_PC	Benign	0.023
FATHMM_MKL	Benign	0.39	N
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D;D;D
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.34	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.49	T
MutationAssessor	Benign	1.2	L;.;.;L;.;L;L;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-3.8	D;D;D;D;D;D;D;D
REVEL	Uncertain	0.49
Sift	Benign	0.10	T;T;T;T;T;T;T;T
Sift4G	Benign	0.58	T;T;T;T;T;T;T;T
Polyphen		1.0	.;.;.;D;.;.;.;.
Vest4		0.57
MutPred		0.43		Gain of catalytic residue at N388 (P = 0);.;.;Gain of catalytic residue at N388 (P = 0);.;Gain of catalytic residue at N388 (P = 0);Gain of catalytic residue at N388 (P = 0);.;
MVP		0.79
MPC		1.4
ClinPred		0.98	D
GERP RS		4.0
Varity_R		0.61
gMVP		0.90

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: rs753816187; hg19: chr12-32884018;