NM_015569.5:c.788C>T

Variant names:

• chr1-172033204-C-T
• rs767005768
• NM_015569.5:c.788C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_015569.5(DNM3):​c.788C>T​(p.Pro263Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000995 in 1,608,544 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. P263P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: DNM3 NM_015569.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.86
• Publications: 0 publications found

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

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.942

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015569.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNM3	NM_015569.5	MANE Select	c.788C>T	p.Pro263Leu	missense	Exon 6 of 21	NP_056384.2
	DNM3	NM_001350204.2		c.788C>T	p.Pro263Leu	missense	Exon 6 of 21	NP_001337133.1	Q9UQ16-1
	DNM3	NM_001136127.3		c.788C>T	p.Pro263Leu	missense	Exon 6 of 20	NP_001129599.1	Q9UQ16-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNM3	ENST00000627582.3	TSL:1 MANE Select	c.788C>T	p.Pro263Leu	missense	Exon 6 of 21	ENSP00000486701.1	Q9UQ16-3
	DNM3	ENST00000367731.5	TSL:1	c.788C>T	p.Pro263Leu	missense	Exon 6 of 20	ENSP00000356705.1	Q9UQ16-2
	DNM3	ENST00000485254.3	TSL:1	c.788C>T	p.Pro263Leu	missense	Exon 6 of 21	ENSP00000429165.2	H0YBC6

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152076 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000834 AC: 2 AN: 239930 AF XY: 0.0000154

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000473

Gnomad NFE exome AF: 0.00000922

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000824 AC: 12 AN: 1456468 Hom.: 0 Cov.: 31 AF XY: 0.00000967 AC XY: 7 AN XY: 723888

African (AFR) AF: 0.00 AC: 0 AN: 33388

American (AMR) AF: 0.00 AC: 0 AN: 44018

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26000

East Asian (EAS) AF: 0.00 AC: 0 AN: 39516

South Asian (SAS) AF: 0.00 AC: 0 AN: 84962

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53108

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.0000108 AC: 12 AN: 1109530

Other (OTH) AF: 0.00 AC: 0 AN: 60186

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152076 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74270

African (AFR) AF: 0.0000483 AC: 2 AN: 41402

American (AMR) AF: 0.0000655 AC: 1 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10594

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.00000828 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	D
Eigen	Pathogenic	0.73
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Uncertain	0.26	D
MutationAssessor	Pathogenic	3.4	M
PhyloP100		7.9
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-7.9	D
REVEL	Pathogenic	0.65
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.78
MutPred		0.80		Gain of MoRF binding (P = 0.1034)
MVP		0.95
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.88
gMVP		0.79
Mutation Taster		=86/14	polymorphism

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

Other links and lift over

dbSNP: rs767005768; hg19: chr1-172002344;