10-99880025-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.4334G>A​(p.Arg1445Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

DNMBP
NM_015221.4 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.998
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]

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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=0.057251602).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
DNMBPNM_015221.4 linkc.4334G>A p.Arg1445Lys missense_variant Exon 16 of 17 ENST00000324109.9 NP_056036.1 Q6XZF7-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
DNMBPENST00000324109.9 linkc.4334G>A p.Arg1445Lys missense_variant Exon 16 of 17 1 NM_015221.4 ENSP00000315659.4 Q6XZF7-1
DNMBPENST00000543621.6 linkc.2198G>A p.Arg733Lys missense_variant Exon 13 of 14 1 ENSP00000443657.2 A0A1C7CYY6
DNMBPENST00000636706.1 linkc.3230G>A p.Arg1077Lys missense_variant Exon 13 of 14 2 ENSP00000489875.1 A0A1B0GTX1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.0000278
AC:
7
AN:
251470
Hom.:
0
AF XY:
0.0000221
AC XY:
3
AN XY:
135910
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000202
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000479
AC:
7
AN:
1461886
Hom.:
0
Cov.:
31
AF XY:
0.00000413
AC XY:
3
AN XY:
727242
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000157
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000378
ExAC
AF:
0.0000165
AC:
2

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Feb 12, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.4334G>A (p.R1445K) 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 4334, causing the arginine (R) at amino acid position 1445 to be replaced by a lysine (K). 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
0.092
BayesDel_addAF
Benign
-0.51
T
BayesDel_noAF
Benign
-0.69
CADD
Benign
8.1
DANN
Benign
0.67
DEOGEN2
Benign
0.018
.;.;T
Eigen
Benign
-1.1
Eigen_PC
Benign
-1.1
FATHMM_MKL
Benign
0.22
N
LIST_S2
Benign
0.52
T;T;T
M_CAP
Benign
0.0050
T
MetaRNN
Benign
0.057
T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Uncertain
2.3
.;.;M
PrimateAI
Benign
0.33
T
PROVEAN
Benign
-0.50
.;.;N
REVEL
Benign
0.047
Sift
Benign
0.11
.;.;T
Sift4G
Benign
0.33
.;.;T
Polyphen
0.69
.;.;P
Vest4
0.064
MVP
0.47
MPC
0.14
ClinPred
0.066
T
GERP RS
2.9
Varity_R
0.054
gMVP
0.16

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: rs751657437; hg19: chr10-101639782; API