1-172048676-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_015569.5(DNM3):c.1261A>G(p.Lys421Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: 9.32

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNM3	NM_015569.5	c.1261A>G	p.Lys421Glu	missense_variant	10/21	ENST00000627582.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNM3	ENST00000627582.3	c.1261A>G	p.Lys421Glu	missense_variant	10/21	1	NM_015569.5	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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

Jun 07, 2023

The c.1261A>G (p.K421E) alteration is located in exon 10 (coding exon 10) of the DNM3 gene. This alteration results from a A to G substitution at nucleotide position 1261, causing the lysine (K) at amino acid position 421 to be replaced by a glutamic acid (E). 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	Uncertain	0.56
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
Cadd	Uncertain	25
Dann	Uncertain	1.0
Eigen	Benign	0.041
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D
M_CAP	Benign	0.059	D
MetaRNN	Uncertain	0.59	D;D;D;D;D;D
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	1.2	L;L;L;L;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.79	T
PROVEAN	Uncertain	-3.0	D;D;.;D;D;D
REVEL	Uncertain	0.45
Sift	Benign	0.56	T;T;.;T;T;T
Sift4G	Benign	1.0	T;T;T;T;T;T
Polyphen		0.18, 0.16, 0.11	.;.;B;B;B;.
Vest4		0.66
MutPred		0.45		Loss of MoRF binding (P = 0.0518);Loss of MoRF binding (P = 0.0518);Loss of MoRF binding (P = 0.0518);Loss of MoRF binding (P = 0.0518);Loss of MoRF binding (P = 0.0518);.;
MVP		0.83
ClinPred		0.98	D
GERP RS		5.6
Varity_R		0.75
gMVP		0.81

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: chr1-172017816;