rs368475266

chr9-128218729-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

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

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, DNM1
• BP4: Computational evidence support a benign effect (MetaRNN=0.40705526).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNM1	NM_004408.4	c.383A>G	p.His128Arg	missense_variant, splice_region_variant	3/22	ENST00000372923.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNM1	ENST00000372923.8	c.383A>G	p.His128Arg	missense_variant, splice_region_variant	3/22	1	NM_004408.4	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.91e-7 AC: 1 AN: 1447688 Hom.: 0 Cov.: 32 AF XY: 0.00000139 AC XY: 1 AN XY: 717632

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000168

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Developmental and epileptic encephalopathy, 31 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 02, 2021

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	D
BayesDel_noAF	Uncertain	-0.010
Cadd	Uncertain	26
Dann	Uncertain	0.98
DEOGEN2	Pathogenic	0.90	D;.;.;.;.;.;T;.;.
Eigen	Benign	0.0094
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.78	T;.;.;T;T;T;T;T;T
M_CAP	Uncertain	0.093	D
MetaRNN	Benign	0.41	T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.50	D
MutationAssessor	Benign	0.95	L;L;L;L;.;L;.;L;.
MutationTaster	Benign	0.99	D;D;D;D;D
PrimateAI	Uncertain	0.74	T
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	D
GERP RS		5.4
Varity_R		0.37
gMVP		0.78

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

LitVar

Other links and lift over

dbSNP: rs368475266; hg19: chr9-130981008; COSMIC: COSV57852970; COSMIC: COSV57852970;