rs769986411

Variant names:

• chr9-128203491-A-C
• rs769986411
• NM_004408.4:c.21A>C

Your query was ambiguous. Multiple possible variants found:

• chr9-128203491-A-C
• chr9-128203491-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.21A>C​(p.Glu7Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DNM1 NM_004408.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.434

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 Uncertain_significance. Variant got 2 ACMG points.

• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.27286625).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNM1	NM_004408.4	c.21A>C	p.Glu7Asp	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.21A>C	p.Glu7Asp	missense_variant	Exon 1 of 22	1	NM_004408.4	ENSP00000362014.4
DNM1	ENST00000634267.2	c.21A>C	p.Glu7Asp	missense_variant	Exon 1 of 22	5		ENSP00000489096.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Uncertain	0.095	D
BayesDel_noAF	Benign	-0.10
CADD	Benign	21
DANN	Benign	0.93
DEOGEN2	Benign	0.42	T;.;.;.;.;.;T;.;.
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.75	D
LIST_S2	Uncertain	0.95	D;.;.;D;D;D;D;D;D
M_CAP	Pathogenic	0.90	D
MetaRNN	Benign	0.27	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.34	T
MutationAssessor	Benign	1.9	L;L;L;L;.;L;.;L;.
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-2.2	N;N;N;N;.;N;.;.;.
REVEL	Uncertain	0.39
Sift	Benign	0.13	T;T;T;T;.;T;.;.;.
Sift4G	Benign	0.18	T;T;T;T;T;T;T;T;T
Polyphen		0.28	B;.;B;.;.;B;.;B;.
Vest4		0.31
MutPred		0.38		Loss of helix (P = 0.1706);Loss of helix (P = 0.1706);Loss of helix (P = 0.1706);Loss of helix (P = 0.1706);Loss of helix (P = 0.1706);Loss of helix (P = 0.1706);Loss of helix (P = 0.1706);Loss of helix (P = 0.1706);Loss of helix (P = 0.1706);
MVP		0.69
MPC		1.2
ClinPred		0.56	D
GERP RS		-7.0
Varity_R		0.25
gMVP		0.70

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs769986411; hg19: chr9-130965770;