10-99879891-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_015221.4(DNMBP):​c.4468G>A​(p.Val1490Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000511 in 1,614,108 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00032 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00053 ( 0 hom. )

Consequence

DNMBP
NM_015221.4 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -5.91
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.022491544).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
DNMBPNM_015221.4 linkuse as main transcriptc.4468G>A p.Val1490Ile missense_variant 16/17 ENST00000324109.9 NP_056036.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
DNMBPENST00000324109.9 linkuse as main transcriptc.4468G>A p.Val1490Ile missense_variant 16/171 NM_015221.4 ENSP00000315659 P1Q6XZF7-1
DNMBPENST00000543621.6 linkuse as main transcriptc.2332G>A p.Val778Ile missense_variant 13/141 ENSP00000443657
DNMBPENST00000636706.1 linkuse as main transcriptc.3364G>A p.Val1122Ile missense_variant 13/142 ENSP00000489875

Frequencies

GnomAD3 genomes
AF:
0.000322
AC:
49
AN:
152214
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000145
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000327
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000544
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.000382
AC:
96
AN:
251424
Hom.:
1
AF XY:
0.000339
AC XY:
46
AN XY:
135884
show subpopulations
Gnomad AFR exome
AF:
0.000123
Gnomad AMR exome
AF:
0.000376
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000980
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000651
Gnomad OTH exome
AF:
0.000651
GnomAD4 exome
AF:
0.000531
AC:
776
AN:
1461894
Hom.:
0
Cov.:
31
AF XY:
0.000535
AC XY:
389
AN XY:
727248
show subpopulations
Gnomad4 AFR exome
AF:
0.000269
Gnomad4 AMR exome
AF:
0.000335
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000696
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000635
Gnomad4 OTH exome
AF:
0.000563
GnomAD4 genome
AF:
0.000322
AC:
49
AN:
152214
Hom.:
0
Cov.:
32
AF XY:
0.000363
AC XY:
27
AN XY:
74362
show subpopulations
Gnomad4 AFR
AF:
0.000145
Gnomad4 AMR
AF:
0.000327
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000544
Gnomad4 OTH
AF:
0.000478
Alfa
AF:
0.000445
Hom.:
0
Bravo
AF:
0.000332
TwinsUK
AF:
0.000809
AC:
3
ALSPAC
AF:
0.000778
AC:
3
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000349
AC:
3
ExAC
AF:
0.000321
AC:
39
EpiCase
AF:
0.000382
EpiControl
AF:
0.000593

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsNov 12, 2021The c.4468G>A (p.V1490I) alteration is located in exon 16 (coding exon 15) of the DNMBP gene. This alteration results from a G to A substitution at nucleotide position 4468, causing the valine (V) at amino acid position 1490 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.075
BayesDel_addAF
Benign
-0.67
T
BayesDel_noAF
Benign
-0.83
CADD
Benign
0.0030
DANN
Benign
0.74
DEOGEN2
Benign
0.010
.;.;T
Eigen
Benign
-1.8
Eigen_PC
Benign
-1.9
FATHMM_MKL
Benign
0.028
N
LIST_S2
Benign
0.57
T;T;T
M_CAP
Benign
0.0037
T
MetaRNN
Benign
0.022
T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
0.83
.;.;L
MutationTaster
Benign
1.0
N;N;N;N
PrimateAI
Benign
0.25
T
PROVEAN
Benign
-0.080
.;.;N
REVEL
Benign
0.015
Sift
Benign
0.61
.;.;T
Sift4G
Benign
0.46
.;.;T
Polyphen
0.0
.;.;B
Vest4
0.032
MVP
0.18
MPC
0.11
ClinPred
0.013
T
GERP RS
-9.7
Varity_R
0.036
gMVP
0.15

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.

Other links and lift over

dbSNP: rs199968530; hg19: chr10-101639648; COSMIC: COSV60635449; API