9-128203609-G-T

Variant names:

• chr9-128203609-G-T
• NM_004408.4:c.139G>T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP2 PP3_Moderate

The NM_004408.4(DNM1):​c.139G>T​(p.Val47Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000144 in 1,391,336 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: DNM1 NM_004408.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.74

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a domain Dynamin-type G (size 266) in uniprot entity DYN1_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in NM_004408.4
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the DNM1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 39 curated pathogenic missense variants (we use a threshold of 10). The gene has 46 curated benign missense variants. Gene score misZ: 5.1795 (above the threshold of 3.09). Trascript score misZ: 5.021 (above the threshold of 3.09). GenCC associations: The gene is linked to developmental and epileptic encephalopathy, 31, undetermined early-onset epileptic encephalopathy, developmental and epileptic encephalopathy 31B, developmental and epileptic encephalopathy, Lennox-Gastaut syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.92

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNM1	NM_004408.4	c.139G>T	p.Val47Leu	missense_variant	Exon 1 of 22	ENST00000372923.8	NP_004399.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNM1	ENST00000372923.8	c.139G>T	p.Val47Leu	missense_variant	Exon 1 of 22	1	NM_004408.4	ENSP00000362014.4
DNM1	ENST00000634267.2	c.139G>T	p.Val47Leu	missense_variant	Exon 1 of 22	5		ENSP00000489096.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000144 AC: 2 AN: 1391336 Hom.: 0 Cov.: 30 AF XY: 0.00000144 AC XY: 1 AN XY: 692260

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: 0.0000217

Gnomad4 NFE exome AF: 9.24e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	D;.;.;.;.;.;T;.;.
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	D;.;.;D;D;D;D;D;D
M_CAP	Pathogenic	0.83	D
MetaRNN	Pathogenic	0.92	D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.75	D
MutationAssessor	Uncertain	2.3	M;M;M;M;.;M;.;M;.
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-2.7	D;D;D;D;.;D;.;.;.
REVEL	Pathogenic	0.82
Sift	Uncertain	0.0040	D;D;D;D;.;D;.;.;.
Sift4G	Uncertain	0.0030	D;D;D;D;D;D;D;D;D
Polyphen		0.97	D;.;D;.;.;B;.;D;.
Vest4		0.63
MutPred		0.92		Gain of ubiquitination at K44 (P = 0.1797);Gain of ubiquitination at K44 (P = 0.1797);Gain of ubiquitination at K44 (P = 0.1797);Gain of ubiquitination at K44 (P = 0.1797);Gain of ubiquitination at K44 (P = 0.1797);Gain of ubiquitination at K44 (P = 0.1797);Gain of ubiquitination at K44 (P = 0.1797);Gain of ubiquitination at K44 (P = 0.1797);Gain of ubiquitination at K44 (P = 0.1797);
MVP		0.92
MPC		1.6
ClinPred		0.99	D
GERP RS		4.1
Varity_R		0.85
gMVP		0.95

Splicing

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-130965888;