1-172068837-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_015569.5(DNM3):c.1354C>G(p.Leu452Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DNM3 NM_015569.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.97

Genes affected

DNM3 (HGNC:29125): (dynamin 3) This gene encodes a member of a family of guanosine triphosphate (GTP)-binding proteins that associate with microtubules and are involved in vesicular transport. The encoded protein functions in the development of megakaryocytes. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2013]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.965

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNM3	NM_015569.5	c.1354C>G	p.Leu452Val	missense_variant	11/21	ENST00000627582.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNM3	ENST00000627582.3	c.1354C>G	p.Leu452Val	missense_variant	11/21	1	NM_015569.5	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 09, 2023

The c.1354C>G (p.L452V) alteration is located in exon 11 (coding exon 11) of the DNM3 gene. This alteration results from a C to G substitution at nucleotide position 1354, causing the leucine (L) at amino acid position 452 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
Cadd	Pathogenic	26
Dann	Uncertain	1.0
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Pathogenic	1.0	D;D;D;D;D;D
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D
MetaSVM	Uncertain	0.68	D
MutationAssessor	Pathogenic	3.2	M;M;M;M;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-2.6	D;D;.;D;D;D
REVEL	Pathogenic	0.77
Sift	Uncertain	0.0010	D;D;.;D;D;D
Sift4G	Uncertain	0.030	D;D;D;D;D;D
Polyphen		0.97, 1.0, 1.0	.;.;D;D;D;.
Vest4		0.56
MutPred		0.89		Gain of MoRF binding (P = 0.089);Gain of MoRF binding (P = 0.089);Gain of MoRF binding (P = 0.089);Gain of MoRF binding (P = 0.089);Gain of MoRF binding (P = 0.089);.;
MVP		0.91
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.83
gMVP		0.86

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-172037977;