rs368475266

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_004408.4(DNM1):c.383A>G(p.His128Arg) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000691 in 1,447,688 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. H128H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

DNM1
NM_004408.4 missense, splice_region

Scores

Splicing: ADA: 0.1089

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.32

Publications

0 publications found

Variant links:

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]

DNM1 Gene-Disease associations (from GenCC):

genetic developmental and epileptic encephalopathy
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
developmental and epileptic encephalopathy, 31A
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
developmental and epileptic encephalopathy, 31B
Inheritance: AR, AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
Lennox-Gastaut syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
undetermined early-onset epileptic encephalopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

DNM1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.40705526).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNM1	NM_004408.4 link	c.383A>G	p.His128Arg	missense_variant, splice_region_variant	Exon 3 of 22	ENST00000372923.8	NP_004399.2	Q05193-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNM1	ENST00000372923.8 link	c.383A>G	p.His128Arg	missense_variant, splice_region_variant	Exon 3 of 22	1	NM_004408.4	ENSP00000362014.4		Q05193-1
DNM1	ENST00000634267.2 link	c.383A>G	p.His128Arg	missense_variant, splice_region_variant	Exon 3 of 22	5		ENSP00000489096.1		A0A0U1RQP1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.91e-7

AC:

AN:

1447688

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

717632

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33144

American (AMR)

AF:

0.00

AC:

AN:

43834

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25776

East Asian (EAS)

AF:

0.00

AC:

AN:

39302

South Asian (SAS)

AF:

0.00

AC:

AN:

85578

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52736

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5714

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1101936

Other (OTH)

AF:

0.0000168

AC:

AN:

59668

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy, 31A

Uncertain:1

Sep 02, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces histidine with arginine at codon 128 of the DNM1 protein (p.His128Arg). The histidine residue is highly conserved and there is a small physicochemical difference between histidine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with DNM1-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.37

BayesDel_addAF

Uncertain

0.16

BayesDel_noAF

Uncertain

-0.010

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Pathogenic

0.90

D;.;.;.;.;.;T;.;.

Eigen

Benign

0.0094

Eigen_PC

Benign

0.13

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.78

T;.;.;T;T;T;T;T;T

M_CAP

Uncertain

0.093

MetaRNN

Benign

0.41

T;T;T;T;T;T;T;T;T

MetaSVM

Uncertain

0.50

MutationAssessor

Benign

0.95

L;L;L;L;.;L;.;L;.

PhyloP100

9.3

PrimateAI

Uncertain

0.74

PROVEAN

Uncertain

-4.2

D;D;D;D;.;D;.;.;.

REVEL

Uncertain

0.47

Sift

Benign

0.086

T;T;T;T;.;T;.;.;.

Sift4G

Benign

0.065

T;T;T;T;T;T;T;T;T

Polyphen

0.088

B;.;B;.;.;B;.;B;.

Vest4

0.35

MVP

0.83

MPC

1.4

ClinPred

0.92

GERP RS

5.4

Varity_R

0.37

gMVP

0.78

Mutation Taster

=62/38

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.11

dbscSNV1_RF

Benign

0.40

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over