chr9-128203516-C-A

Position:

• chr9-128203516-C-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_004408.4(DNM1):​c.46C>A​(p.Leu16Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00753 in 1,540,792 control chromosomes in the GnomAD database, including 292 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0070 (36 hom., cov: 31)
  • Exomes 𝑓: 0.0076 (256 hom.)
• Consequence: DNM1 NM_004408.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.54

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 Benign. Variant got -19 ACMG points.

• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0020967126).
• BP6: Variant 9-128203516-C-A is Benign according to our data. Variant chr9-128203516-C-A is described in ClinVar as [Benign]. Clinvar id is 380950.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0917 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNM1	NM_004408.4	c.46C>A	p.Leu16Met	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.46C>A	p.Leu16Met	missense_variant	1/22	1	NM_004408.4	ENSP00000362014.4
DNM1	ENST00000634267.2	c.46C>A	p.Leu16Met	missense_variant	1/22	5		ENSP00000489096.1

Frequencies

GnomAD3 genomes AF: 0.00705 AC: 1071 AN: 151860 Hom.: 36 Cov.: 31

Gnomad AFR AF: 0.00106

Gnomad AMI AF: 0.0286

Gnomad AMR AF: 0.00544

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0992

Gnomad SAS AF: 0.0271

Gnomad FIN AF: 0.000668

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.00374

Gnomad OTH AF: 0.00575

GnomAD3 exomes AF: 0.0138 AC: 2346 AN: 170580 Hom.: 53 AF XY: 0.0135 AC XY: 1283 AN XY: 95134

Gnomad AFR exome AF: 0.00181

Gnomad AMR exome AF: 0.0163

Gnomad ASJ exome AF: 0.000256

Gnomad EAS exome AF: 0.0947

Gnomad SAS exome AF: 0.0272

Gnomad FIN exome AF: 0.000923

Gnomad NFE exome AF: 0.00501

Gnomad OTH exome AF: 0.00814

GnomAD4 exome AF: 0.00758 AC: 10530 AN: 1388824 Hom.: 256 Cov.: 30 AF XY: 0.00808 AC XY: 5572 AN XY: 689566

Gnomad4 AFR exome AF: 0.000942

Gnomad4 AMR exome AF: 0.0131

Gnomad4 ASJ exome AF: 0.000375

Gnomad4 EAS exome AF: 0.105

Gnomad4 SAS exome AF: 0.0273

Gnomad4 FIN exome AF: 0.00110

Gnomad4 NFE exome AF: 0.00378

Gnomad4 OTH exome AF: 0.00764

GnomAD4 genome AF: 0.00703 AC: 1068 AN: 151968 Hom.: 36 Cov.: 31 AF XY: 0.00808 AC XY: 600 AN XY: 74284

Gnomad4 AFR AF: 0.00106

Gnomad4 AMR AF: 0.00543

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0988

Gnomad4 SAS AF: 0.0271

Gnomad4 FIN AF: 0.000668

Gnomad4 NFE AF: 0.00374

Gnomad4 OTH AF: 0.00617

Alfa AF: 0.00776 Hom.: 29

Bravo AF: 0.00771

ESP6500AA AF: 0.00137 AC: 6

ESP6500EA AF: 0.00316 AC: 27

ExAC AF: 0.0143 AC: 1720

Asia WGS AF: 0.0420 AC: 141 AN: 3388

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Developmental and epileptic encephalopathy, 31A Benign:2

Benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Feb 18, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 14, 2017	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 22, 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. -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 22, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Uncertain	0.53	D;.;.;.;.;.;T;.;.
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.75	D
LIST_S2	Uncertain	0.93	D;.;.;D;D;D;D;D;D
MetaRNN	Benign	0.0021	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.36	T
MutationAssessor	Uncertain	2.7	M;M;M;M;.;M;.;M;.
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-1.6	N;N;N;N;.;N;.;.;.
REVEL	Uncertain	0.52
Sift	Uncertain	0.019	D;D;D;D;.;D;.;.;.
Sift4G	Uncertain	0.029	D;D;D;D;D;D;D;D;D
Polyphen		0.012	B;.;B;.;.;B;.;B;.
Vest4		0.093
MPC		1.8
ClinPred		0.029	T
GERP RS		1.9
Varity_R		0.27
gMVP		0.76

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs61757224; hg19: chr9-130965795;