Genetic Variant DNMBP:p.Glu1575Glu (chr10-99877160-C-T) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BS1BS2

The NM_015221.4(DNMBP):c.4725G>A(p.Glu1575Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0225 in 1,609,802 control chromosomes in the GnomAD database, including 435 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.017 ( 23 hom., cov: 32)

Exomes 𝑓: 0.023 ( 412 hom. )

Consequence

DNMBP
NM_015221.4 synonymous

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 0.350

Variant links:

Genes affected

DNMBP (HGNC:30373): (dynamin binding protein) This gene encodes a protein belonging to the guanine nucleotide exchange factor family, and which regulates the configuration of cell junctions. It contains multiple binding sites for dynamin and thus links dynamin to actin regulatory proteins. Polymorphisms in this gene have been linked to Alzheimer's disease in some populations, though there are conflicting reports of such linkages in other populations. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2015]

DNMBP links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.48).

BP6

Variant 10-99877160-C-T is Benign according to our data. Variant chr10-99877160-C-T is described in ClinVar as [Benign]. Clinvar id is 3038273.Status of the report is no_assertion_criteria_provided, 0 stars.

BP7

Synonymous conserved (PhyloP=0.35 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0172 (2620/152240) while in subpopulation NFE AF= 0.0248 (1685/68020). AF 95% confidence interval is 0.0238. There are 23 homozygotes in gnomad4. There are 1258 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 23 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNMBP	NM_015221.4 link	c.4725G>A	p.Glu1575Glu	synonymous_variant	Exon 17 of 17	ENST00000324109.9	NP_056036.1	Q6XZF7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
DNMBP	ENST00000324109.9 link	c.4725G>A	p.Glu1575Glu	synonymous_variant	Exon 17 of 17	1	NM_015221.4	ENSP00000315659.4	Q6XZF7-1
DNMBP	ENST00000543621.6 link	c.2589G>A	p.Glu863Glu	synonymous_variant	Exon 14 of 14	1		ENSP00000443657.2	A0A1C7CYY6
DNMBP	ENST00000636706.1 link	c.3621G>A	p.Glu1207Glu	synonymous_variant	Exon 14 of 14	2		ENSP00000489875.1	A0A1B0GTX1

Frequencies

GnomAD3 genomes

AF:

0.0172

AC:

2623

AN:

152122

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00418

Gnomad AMI

AF:

0.0482

Gnomad AMR

AF:

0.0136

Gnomad ASJ

AF:

0.0245

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0104

Gnomad FIN

AF:

0.0329

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0248

Gnomad OTH

AF:

0.0110

GnomAD3 exomes

AF:

0.0185

AC:

4529

AN:

245038

Hom.:

AF XY:

0.0185

AC XY:

2447

AN XY:

132466

show subpopulations

Gnomad AFR exome

AF:

0.00395

Gnomad AMR exome

AF:

0.00654

Gnomad ASJ exome

AF:

0.0292

Gnomad EAS exome

AF:

0.0000563

Gnomad SAS exome

AF:

0.00973

Gnomad FIN exome

AF:

0.0323

Gnomad NFE exome

AF:

0.0255

Gnomad OTH exome

AF:

0.0207

GnomAD4 exome

AF:

0.0231

AC:

33664

AN:

1457562

Hom.:

412

Cov.:

AF XY:

0.0227

AC XY:

16446

AN XY:

724952

show subpopulations

Gnomad4 AFR exome

AF:

0.00354

Gnomad4 AMR exome

AF:

0.00760

Gnomad4 ASJ exome

AF:

0.0270

Gnomad4 EAS exome

AF:

0.0000254

Gnomad4 SAS exome

AF:

0.00939

Gnomad4 FIN exome

AF:

0.0341

Gnomad4 NFE exome

AF:

0.0258

Gnomad4 OTH exome

AF:

0.0188

GnomAD4 genome

AF:

0.0172

AC:

2620

AN:

152240

Hom.:

Cov.:

AF XY:

0.0169

AC XY:

1258

AN XY:

74432

show subpopulations

Gnomad4 AFR

AF:

0.00416

Gnomad4 AMR

AF:

0.0136

Gnomad4 ASJ

AF:

0.0245

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00996

Gnomad4 FIN

AF:

0.0329

Gnomad4 NFE

AF:

0.0248

Gnomad4 OTH

AF:

0.0109

Alfa

AF:

0.0222

Hom.:

Bravo

AF:

0.0154

Asia WGS

AF:

0.00433

AC:

AN:

3478

EpiCase

AF:

0.0236

EpiControl

AF:

0.0235

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

DNMBP-related disorder

Benign:1

Feb 21, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.48

CADD

Benign

8.2

DANN

Benign

0.40

Splicing

Name

Calibrated prediction

Score

Prediction

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over