rs35048348

Variant names:

• chr9-128222530-C-T
• rs35048348
• NM_004408.4:c.1062C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_004408.4(DNM1):​c.1062C>T​(p.Tyr354Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.079 in 1,614,074 control chromosomes in the GnomAD database, including 5,349 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.081 (517 hom., cov: 32)
  • Exomes 𝑓: 0.079 (4832 hom.)
• Consequence: DNM1 NM_004408.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.607
• Publications: 12 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: AR, AD Classification: DEFINITIVE, MODERATE 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: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 9-128222530-C-T is Benign according to our data. Variant chr9-128222530-C-T is described in ClinVar as Benign. ClinVar VariationId is 380913.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.607 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.102 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004408.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNM1	NM_004408.4	MANE Select	c.1062C>T	p.Tyr354Tyr	synonymous	Exon 8 of 22	NP_004399.2	Q05193-1
	DNM1	NM_001374269.1		c.1062C>T	p.Tyr354Tyr	synonymous	Exon 8 of 22	NP_001361198.1	A0A994J7J4
	DNM1	NM_001288739.2		c.1062C>T	p.Tyr354Tyr	synonymous	Exon 8 of 22	NP_001275668.1	Q05193-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNM1	ENST00000372923.8	TSL:1 MANE Select	c.1062C>T	p.Tyr354Tyr	synonymous	Exon 8 of 22	ENSP00000362014.4	Q05193-1
	DNM1	ENST00000486160.3	TSL:1	c.1062C>T	p.Tyr354Tyr	synonymous	Exon 8 of 22	ENSP00000420045.1	Q05193-2
	DNM1	ENST00000634267.2	TSL:5	c.1062C>T	p.Tyr354Tyr	synonymous	Exon 8 of 22	ENSP00000489096.1	A0A0U1RQP1

Frequencies

GnomAD3 genomes AF: 0.0808 AC: 12295 AN: 152106 Hom.: 515 Cov.: 32

Gnomad AFR AF: 0.104

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.0638

Gnomad ASJ AF: 0.121

Gnomad EAS AF: 0.00251

Gnomad SAS AF: 0.0905

Gnomad FIN AF: 0.0576

Gnomad MID AF: 0.117

Gnomad NFE AF: 0.0778

Gnomad OTH AF: 0.0850

GnomAD2 exomes AF: 0.0690 AC: 17352 AN: 251424 AF XY: 0.0708

Gnomad AFR exome AF: 0.105

Gnomad AMR exome AF: 0.0430

Gnomad ASJ exome AF: 0.121

Gnomad EAS exome AF: 0.00234

Gnomad FIN exome AF: 0.0574

Gnomad NFE exome AF: 0.0738

Gnomad OTH exome AF: 0.0797

GnomAD4 exome AF: 0.0788 AC: 115146 AN: 1461850 Hom.: 4832 Cov.: 33 AF XY: 0.0796 AC XY: 57886 AN XY: 727230

African (AFR) AF: 0.110 AC: 3687 AN: 33478

American (AMR) AF: 0.0456 AC: 2039 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.124 AC: 3244 AN: 26136

East Asian (EAS) AF: 0.00222 AC: 88 AN: 39700

South Asian (SAS) AF: 0.0913 AC: 7877 AN: 86258

European-Finnish (FIN) AF: 0.0588 AC: 3139 AN: 53406

Middle Eastern (MID) AF: 0.103 AC: 596 AN: 5768

European-Non Finnish (NFE) AF: 0.0806 AC: 89584 AN: 1111986

Other (OTH) AF: 0.0810 AC: 4892 AN: 60396

GnomAD4 genome AF: 0.0808 AC: 12307 AN: 152224 Hom.: 517 Cov.: 32 AF XY: 0.0790 AC XY: 5880 AN XY: 74422

African (AFR) AF: 0.104 AC: 4334 AN: 41526

American (AMR) AF: 0.0636 AC: 973 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.121 AC: 421 AN: 3472

East Asian (EAS) AF: 0.00252 AC: 13 AN: 5162

South Asian (SAS) AF: 0.0912 AC: 440 AN: 4826

European-Finnish (FIN) AF: 0.0576 AC: 611 AN: 10614

Middle Eastern (MID) AF: 0.119 AC: 35 AN: 294

European-Non Finnish (NFE) AF: 0.0778 AC: 5290 AN: 68004

Other (OTH) AF: 0.0855 AC: 181 AN: 2116

Alfa AF: 0.0797 Hom.: 613

Bravo AF: 0.0815

Asia WGS AF: 0.0580 AC: 201 AN: 3478

EpiCase AF: 0.0763

EpiControl AF: 0.0772

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Developmental and epileptic encephalopathy, 31A (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	5.8
DANN	Benign	0.91
PhyloP100		-0.61
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=91/9	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs35048348; hg19: chr9-130984809; COSMIC: COSV57852866; COSMIC: COSV57852866;