9-128250826-C-T

Variant names:

• chr9-128250826-C-T
• rs935756107
• NM_004408.4:c.2420C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004408.4(DNM1):​c.2420C>T​(p.Ser807Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000427 in 1,172,250 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S807C) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000043 (0 hom.)
• Consequence: DNM1 NM_004408.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.42
• Publications: 0 publications found

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]

DNM1 Gene-Disease associations (from GenCC):

• genetic developmental and epileptic encephalopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• developmental and epileptic encephalopathy, 31A

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• developmental and epileptic encephalopathy, 31B

  Inheritance: AR, AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• Lennox-Gastaut syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• undetermined early-onset epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1672715).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNM1	NM_004408.4	c.2420C>T	p.Ser807Phe	missense_variant	Exon 21 of 22	ENST00000372923.8	NP_004399.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNM1	ENST00000372923.8	c.2420C>T	p.Ser807Phe	missense_variant	Exon 21 of 22	1	NM_004408.4	ENSP00000362014.4
DNM1	ENST00000634267.2	c.2420C>T	p.Ser807Phe	missense_variant	Exon 21 of 22	5		ENSP00000489096.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000427 AC: 5 AN: 1172250 Hom.: 0 Cov.: 31 AF XY: 0.00000883 AC XY: 5 AN XY: 566404

African (AFR) AF: 0.0000855 AC: 2 AN: 23388

American (AMR) AF: 0.00 AC: 0 AN: 8912

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15772

East Asian (EAS) AF: 0.00 AC: 0 AN: 27324

South Asian (SAS) AF: 0.0000762 AC: 3 AN: 39370

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 26426

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3304

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 979688

Other (OTH) AF: 0.00 AC: 0 AN: 48066

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Pathogenic	26
DANN	Uncertain	0.98
DEOGEN2	Benign	0.36	T;.;.;.;.;.;T;.;.
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.093
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.95	D;.;.;D;D;D;D;D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.17	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L;L;L;L;.;L;.;L;.
PhyloP100		5.4
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-1.4	N;N;N;N;.;N;.;.;.
REVEL	Benign	0.097
Sift	Benign	0.044	D;D;D;D;.;D;.;.;.
Sift4G	Uncertain	0.060	T;T;T;T;T;T;T;T;T
Polyphen		0.23	B;.;B;.;.;.;.;B;.
Vest4		0.20
MutPred		0.36		Loss of glycosylation at S807 (P = 0.0045);Loss of glycosylation at S807 (P = 0.0045);Loss of glycosylation at S807 (P = 0.0045);Loss of glycosylation at S807 (P = 0.0045);.;Loss of glycosylation at S807 (P = 0.0045);.;Loss of glycosylation at S807 (P = 0.0045);Loss of glycosylation at S807 (P = 0.0045);
MVP		0.39
MPC		1.3
ClinPred		0.51	D
GERP RS		3.7
PromoterAI		0.032	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.23
gMVP		0.049
Mutation Taster		=90/10	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs935756107; hg19: chr9-131013105;