rs35048348

Positions:

• chr9-128222530-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_004408.4(DNM1):​c.1062C>T​(p.Tyr354=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.079 in 1,614,074 control chromosomes in the GnomAD database, including 5,349 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.081 (517 hom., cov: 32)
  • Exomes 𝑓: 0.079 (4832 hom.)
• Consequence: DNM1 NM_004408.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.607

Genes affected

DNM1 (HGNC:2972): (dynamin 1) This gene encodes a member of the dynamin subfamily of GTP-binding proteins. The encoded protein possesses unique mechanochemical properties used to tubulate and sever membranes, and is involved in clathrin-mediated endocytosis and other vesicular trafficking processes. Actin and other cytoskeletal proteins act as binding partners for the encoded protein, which can also self-assemble leading to stimulation of GTPase activity. More than sixty highly conserved copies of the 3' region of this gene are found elsewhere in the genome, particularly on chromosomes Y and 15. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 9-128222530-C-T is Benign according to our data. Variant chr9-128222530-C-T is described in ClinVar as [Benign]. Clinvar id is 380913.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.607 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.102 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNM1	NM_004408.4	c.1062C>T	p.Tyr354=	synonymous_variant	8/22	ENST00000372923.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNM1	ENST00000372923.8	c.1062C>T	p.Tyr354=	synonymous_variant	8/22	1	NM_004408.4	A1

Frequencies

GnomAD3 genomes AF: 0.0808 AC: 12295 AN: 152106 Hom.: 515 Cov.: 32

Gnomad AFR AF: 0.104

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.0638

Gnomad ASJ AF: 0.121

Gnomad EAS AF: 0.00251

Gnomad SAS AF: 0.0905

Gnomad FIN AF: 0.0576

Gnomad MID AF: 0.117

Gnomad NFE AF: 0.0778

Gnomad OTH AF: 0.0850

GnomAD3 exomes AF: 0.0690 AC: 17352 AN: 251424 Hom.: 686 AF XY: 0.0708 AC XY: 9623 AN XY: 135906

Gnomad AFR exome AF: 0.105

Gnomad AMR exome AF: 0.0430

Gnomad ASJ exome AF: 0.121

Gnomad EAS exome AF: 0.00234

Gnomad SAS exome AF: 0.0907

Gnomad FIN exome AF: 0.0574

Gnomad NFE exome AF: 0.0738

Gnomad OTH exome AF: 0.0797

GnomAD4 exome AF: 0.0788 AC: 115146 AN: 1461850 Hom.: 4832 Cov.: 33 AF XY: 0.0796 AC XY: 57886 AN XY: 727230

Gnomad4 AFR exome AF: 0.110

Gnomad4 AMR exome AF: 0.0456

Gnomad4 ASJ exome AF: 0.124

Gnomad4 EAS exome AF: 0.00222

Gnomad4 SAS exome AF: 0.0913

Gnomad4 FIN exome AF: 0.0588

Gnomad4 NFE exome AF: 0.0806

Gnomad4 OTH exome AF: 0.0810

GnomAD4 genome AF: 0.0808 AC: 12307 AN: 152224 Hom.: 517 Cov.: 32 AF XY: 0.0790 AC XY: 5880 AN XY: 74422

Gnomad4 AFR AF: 0.104

Gnomad4 AMR AF: 0.0636

Gnomad4 ASJ AF: 0.121

Gnomad4 EAS AF: 0.00252

Gnomad4 SAS AF: 0.0912

Gnomad4 FIN AF: 0.0576

Gnomad4 NFE AF: 0.0778

Gnomad4 OTH AF: 0.0855

Alfa AF: 0.0827 Hom.: 361

Bravo AF: 0.0815

Asia WGS AF: 0.0580 AC: 201 AN: 3478

EpiCase AF: 0.0763

EpiControl AF: 0.0772

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 05, 2016

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Developmental and epileptic encephalopathy, 31 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 16, 2016

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Apr 20, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	5.8
DANN	Benign	0.91
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs35048348; hg19: chr9-130984809; COSMIC: COSV57852866; COSMIC: COSV57852866;