9-128203525-G-T

Position:

• chr9-128203525-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_004408.4(DNM1):​c.55G>T​(p.Ala19Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000719 in 1,389,976 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: DNM1 NM_004408.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.80

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]

CIZ1 (HGNC:16744): (CDKN1A interacting zinc finger protein 1) The protein encoded by this gene is a zinc finger DNA binding protein that interacts with CIP1, part of a complex with cyclin E. The encoded protein may regulate the cellular localization of CIP1. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2012]

CIZ1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), DNM1. . Gene score misZ 5.1795 (greater than the threshold 3.09). Trascript score misZ 5.021 (greater than threshold 3.09). GenCC has associacion of gene with developmental and epileptic encephalopathy, 31, undetermined early-onset epileptic encephalopathy, developmental and epileptic encephalopathy 31B, developmental and epileptic encephalopathy, Lennox-Gastaut syndrome.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNM1	NM_004408.4	c.55G>T	p.Ala19Ser	missense_variant	1/22	ENST00000372923.8	NP_004399.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNM1	ENST00000372923.8	c.55G>T	p.Ala19Ser	missense_variant	1/22	1	NM_004408.4	ENSP00000362014.4
DNM1	ENST00000634267.2	c.55G>T	p.Ala19Ser	missense_variant	1/22	5		ENSP00000489096.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.19e-7 AC: 1 AN: 1389976 Hom.: 0 Cov.: 30 AF XY: 0.00000145 AC XY: 1 AN XY: 690382

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: 0.0000127

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Mar 23, 2017

The A19S variant in the DNM1 gene has not been reported previously as a pathogenic variant, nor asa benign variant, to our knowledge. The A19S variant is not observed in large population cohorts (Leket al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The A19S variant is anon-conservative amino acid substitution, which is likely to impact secondary protein structure asthese residues differ in polarity, charge, size and/or other properties. This substitution occurs at aposition that is conserved across species and in silico analysis predicts this variant is probablydamaging to the protein structure/function. We interpret A19S as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.66	D;.;.;.;.;.;T;.;.
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.97	D;.;.;D;D;D;D;D;D
M_CAP	Pathogenic	0.96	D
MetaRNN	Uncertain	0.63	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.1	M;M;M;M;.;M;.;M;.
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-2.6	D;D;D;D;.;D;.;.;.
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0020	D;D;D;D;.;D;.;.;.
Sift4G	Uncertain	0.0050	D;D;D;D;D;D;D;D;D
Polyphen		0.98	D;.;D;.;.;D;.;D;.
Vest4		0.37
MutPred		0.49		Gain of disorder (P = 0.0887);Gain of disorder (P = 0.0887);Gain of disorder (P = 0.0887);Gain of disorder (P = 0.0887);Gain of disorder (P = 0.0887);Gain of disorder (P = 0.0887);Gain of disorder (P = 0.0887);Gain of disorder (P = 0.0887);Gain of disorder (P = 0.0887);
MVP		0.84
MPC		2.3
ClinPred		0.98	D
GERP RS		3.9
Varity_R		0.70
gMVP		0.57

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1131691398; hg19: chr9-130965804;