1-172033176-G-T

Position:

• chr1-172033176-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 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 (★).

• 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

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]

DNM3 (HGNC:):

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	Protein	UniProt
DNM3	NM_015569.5	c.760G>T	p.Ala254Ser	missense_variant	6/21	ENST00000627582.3	NP_056384.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNM3	ENST00000627582.3	c.760G>T	p.Ala254Ser	missense_variant	6/21	1	NM_015569.5	ENSP00000486701.1

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

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: 0.0000117

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

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

Aug 01, 2022

The c.760G>T (p.A254S) alteration is located in exon 6 (coding exon 6) of the DNM3 gene. This alteration results from a G to T substitution at nucleotide position 760, causing the alanine (A) at amino acid position 254 to be replaced by a serine (S). 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	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;.;.;T;.
Eigen	Benign	0.11
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;D;D;D;D;D
M_CAP	Benign	0.064	D
MetaRNN	Uncertain	0.66	D;D;D;D;D;D
MetaSVM	Uncertain	0.27	D
MutationAssessor	Benign	1.8	L;L;L;L;.;.
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-2.2	N;N;.;N;N;N
REVEL	Uncertain	0.36
Sift	Benign	0.14	T;T;.;T;T;T
Sift4G	Benign	0.69	T;T;T;T;T;T
Polyphen		0.28, 0.14, 0.012	.;.;B;B;B;.
Vest4		0.32
MutPred		0.41		Gain of phosphorylation at A254 (P = 0.0499);Gain of phosphorylation at A254 (P = 0.0499);Gain of phosphorylation at A254 (P = 0.0499);Gain of phosphorylation at A254 (P = 0.0499);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

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-172002316;