1-172033176-G-T

Variant names:

• chr1-172033176-G-T
• rs759897946
• NM_015569.5:c.760G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_015569.5(DNM3):​c.760G>T​(p.Ala254Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,458,902 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A254T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: DNM3 NM_015569.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.00
• 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: Uncertain_significance. The variant received 2 ACMG points.

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

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.760G>T	p.Ala254Ser	missense	Exon 6 of 21	NP_056384.2
	DNM3	NM_001350204.2		c.760G>T	p.Ala254Ser	missense	Exon 6 of 21	NP_001337133.1	Q9UQ16-1
	DNM3	NM_001136127.3		c.760G>T	p.Ala254Ser	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.760G>T	p.Ala254Ser	missense	Exon 6 of 21	ENSP00000486701.1	Q9UQ16-3
	DNM3	ENST00000367731.5	TSL:1	c.760G>T	p.Ala254Ser	missense	Exon 6 of 20	ENSP00000356705.1	Q9UQ16-2
	DNM3	ENST00000485254.3	TSL:1	c.760G>T	p.Ala254Ser	missense	Exon 6 of 21	ENSP00000429165.2	H0YBC6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1458902 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 725386

African (AFR) AF: 0.00 AC: 0 AN: 33434

American (AMR) AF: 0.00 AC: 0 AN: 44306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26074

East Asian (EAS) AF: 0.00 AC: 0 AN: 39620

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85522

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53248

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110662

Other (OTH) AF: 0.00 AC: 0 AN: 60270

GnomAD4 genome Cov.: 32

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	0.16
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.64	D
Eigen	Benign	0.11
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.064	D
MetaRNN	Uncertain	0.66	D
MetaSVM	Uncertain	0.27	D
MutationAssessor	Benign	1.8	L
PhyloP100		8.0
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-2.2	N
REVEL	Uncertain	0.36
Sift	Benign	0.14	T
Sift4G	Benign	0.69	T
Polyphen		0.28	B
Vest4		0.32
MutPred		0.41		Gain of phosphorylation at A254 (P = 0.0499)
MVP		0.89
ClinPred		0.96	D
GERP RS		4.7
Varity_R		0.45
gMVP		0.47
Mutation Taster		=68/32	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs759897946; hg19: chr1-172002316;