Genetic Variant DNM3:p.Asn686Asn (chr1-172379182-C-T) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_015569.5(DNM3):c.2058C>T(p.Asn686Asn) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00172 in 1,599,870 control chromosomes in the GnomAD database, including 38 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0088 ( 15 hom., cov: 32)

Exomes 𝑓: 0.00098 ( 23 hom. )

Consequence

DNM3
NM_015569.5 splice_region, synonymous

Scores

Splicing: ADA: 0.0007614

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.297

Publications

0 publications found

Variant links:

Genes affected

DNM3 (HGNC:29125): (dynamin 3) This gene encodes a member of a family of guanosine triphosphate (GTP)-binding proteins that associate with microtubules and are involved in vesicular transport. The encoded protein functions in the development of megakaryocytes. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2013]

DNM3 links:

PIGC (HGNC:8960): (phosphatidylinositol glycan anchor biosynthesis class C) This gene encodes an endoplasmic reticulum associated protein that is involved in glycosylphosphatidylinositol (GPI) lipid anchor biosynthesis. The GPI lipid anchor is a glycolipid found on many blood cells and serves to anchor proteins to the cell surface. The encoded protein is one subunit of the GPI N-acetylglucosaminyl (GlcNAc) transferase that transfers GlcNAc to phosphatidylinositol (PI) on the cytoplasmic side of the endoplasmic reticulum. Two alternatively spliced transcripts that encode the same protein have been found for this gene. A pseudogene on chromosome 11 has also been characterized. [provided by RefSeq, Jul 2008]

PIGC Gene-Disease associations (from GenCC):

glycosylphosphatidylinositol biosynthesis defect 16
Inheritance: AR Classification: STRONG, LIMITED Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics
autosomal recessive non-syndromic intellectual disability
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

PIGC links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BP6

Variant 1-172379182-C-T is Benign according to our data. Variant chr1-172379182-C-T is described in ClinVar as Benign. ClinVar VariationId is 791227.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.297 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00876 (1332/152104) while in subpopulation AFR AF = 0.0296 (1230/41536). AF 95% confidence interval is 0.0282. There are 15 homozygotes in GnomAd4. There are 605 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 15 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015569.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DNM3	NM_015569.5	MANE Select	c.2058C>T	p.Asn686Asn	splice_region synonymous	Exon 18 of 21	NP_056384.2
DNM3	NM_001350204.2		c.2076C>T	p.Asn692Asn	splice_region synonymous	Exon 18 of 21	NP_001337133.1	Q9UQ16-1
DNM3	NM_001136127.3		c.2046C>T	p.Asn682Asn	splice_region synonymous	Exon 17 of 20	NP_001129599.1	Q9UQ16-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DNM3	ENST00000627582.3	TSL:1 MANE Select	c.2058C>T	p.Asn686Asn	splice_region synonymous	Exon 18 of 21	ENSP00000486701.1	Q9UQ16-3
DNM3	ENST00000367731.5	TSL:1	c.2046C>T	p.Asn682Asn	splice_region synonymous	Exon 17 of 20	ENSP00000356705.1	Q9UQ16-2
DNM3	ENST00000485254.3	TSL:1	c.2076C>T	p.Asn692Asn	splice_region synonymous	Exon 18 of 21	ENSP00000429165.2	H0YBC6

Frequencies

GnomAD3 genomes

AF:

0.00870

AC:

1323

AN:

151986

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0295

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00427

Gnomad ASJ

AF:

0.00404

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000883

Gnomad OTH

AF:

0.00718

GnomAD2 exomes

AF:

0.00240

AC:

558

AN:

232490

AF XY:

0.00197

show subpopulations

Gnomad AFR exome

AF:

0.0318

Gnomad AMR exome

AF:

0.00152

Gnomad ASJ exome

AF:

0.00348

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000152

Gnomad OTH exome

AF:

0.000879

GnomAD4 exome

AF:

0.000977

AC:

1415

AN:

1447766

Hom.:

Cov.:

AF XY:

0.000844

AC XY:

607

AN XY:

718950

show subpopulations

African (AFR)

AF:

0.0298

AC:

987

AN:

33066

American (AMR)

AF:

0.00187

AC:

AN:

42794

Ashkenazi Jewish (ASJ)

AF:

0.00362

AC:

AN:

25678

East Asian (EAS)

AF:

0.00

AC:

AN:

39406

South Asian (SAS)

AF:

0.0000357

AC:

AN:

84072

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52902

Middle Eastern (MID)

AF:

0.000698

AC:

AN:

5730

European-Non Finnish (NFE)

AF:

0.000101

AC:

111

AN:

1104286

Other (OTH)

AF:

0.00229

AC:

137

AN:

59832

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

122

183

244

305

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

108

144

180

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00876

AC:

1332

AN:

152104

Hom.:

Cov.:

AF XY:

0.00814

AC XY:

605

AN XY:

74364

show subpopulations

African (AFR)

AF:

0.0296

AC:

1230

AN:

41536

American (AMR)

AF:

0.00426

AC:

AN:

15252

Ashkenazi Jewish (ASJ)

AF:

0.00404

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5166

South Asian (SAS)

AF:

0.000207

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10594

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000883

AC:

AN:

67948

Other (OTH)

AF:

0.00710

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

140

211

281

351

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00486

Hom.:

Bravo

AF:

0.0101

Asia WGS

AF:

0.00231

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

4.1

(source)

DANN

Benign

0.73

PhyloP100

-0.30

Mutation Taster

=70/30

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00076

dbscSNV1_RF

Benign

0.30

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over