12-32679392-A-G

Variant names:

• chr12-32679392-A-G
• rs1592548168
• NM_001278464.2:c.29A>G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_012062.5(DNM1L):​c.29A>G​(p.Lys10Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,522 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: DNM1L NM_012062.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.73

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the DNM1L gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 31 curated pathogenic missense variants (we use a threshold of 10). The gene has 9 curated benign missense variants. Gene score misZ: 3.8282 (above the threshold of 3.09). Trascript score misZ: 5.3198 (above the threshold of 3.09). GenCC associations: The gene is linked to encephalopathy, lethal, due to defective mitochondrial peroxisomal fission 1, encephalopathy due to mitochondrial and peroxisomal fission defect, optic atrophy 5, Leigh syndrome, autosomal dominant optic atrophy, classic form.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNM1L	NM_001278464.2	c.29A>G	p.Lys10Arg	missense_variant	Exon 1 of 21	ENST00000553257.6	NP_001265393.1
DNM1L	NM_012062.5	c.29A>G	p.Lys10Arg	missense_variant	Exon 1 of 20	ENST00000549701.6	NP_036192.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNM1L	ENST00000553257.6	c.29A>G	p.Lys10Arg	missense_variant	Exon 1 of 21	2	NM_001278464.2	ENSP00000449089.1
DNM1L	ENST00000549701.6	c.29A>G	p.Lys10Arg	missense_variant	Exon 1 of 20	1	NM_012062.5	ENSP00000450399.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461522 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727096

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: 0.00000180

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000283 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Feb 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 10 of the DNM1L protein (p.Lys10Arg). 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. ClinVar contains an entry for this variant (Variation ID: 1381221). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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	Benign	0.14
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.51	.;.;D;T;.;T;.;.;.;T
Eigen	Benign	-0.11
Eigen_PC	Benign	0.031
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.95	D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.38	D
MetaRNN	Uncertain	0.51	D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.17	D
MutationAssessor	Benign	1.5	L;L;L;.;L;.;.;L;L;.
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-2.1	N;N;N;N;N;N;N;N;N;N
REVEL	Uncertain	0.38
Sift	Benign	0.094	T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.15	T;T;T;T;T;T;T;T;T;T
Polyphen		0.12	.;.;B;.;.;.;.;.;.;.
Vest4		0.68
MutPred		0.41		Gain of catalytic residue at I5 (P = 7e-04);Gain of catalytic residue at I5 (P = 7e-04);Gain of catalytic residue at I5 (P = 7e-04);Gain of catalytic residue at I5 (P = 7e-04);Gain of catalytic residue at I5 (P = 7e-04);Gain of catalytic residue at I5 (P = 7e-04);Gain of catalytic residue at I5 (P = 7e-04);Gain of catalytic residue at I5 (P = 7e-04);Gain of catalytic residue at I5 (P = 7e-04);Gain of catalytic residue at I5 (P = 7e-04);
MVP		0.92
MPC		0.93
ClinPred		0.95	D
GERP RS		3.5
Varity_R		0.34
gMVP		0.74

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: rs1592548168; hg19: chr12-32832326;