10-99955285-T-C

Position:

• chr10-99955285-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015221.4(DNMBP):​c.2189A>G​(p.Glu730Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DNMBP NM_015221.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.71

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-AS1 (HGNC:20431): (DNMBP antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17130023).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNMBP	NM_015221.4	c.2189A>G	p.Glu730Gly	missense_variant	4/17	ENST00000324109.9
DNMBP-AS1	NR_024130.3	n.177-389T>C		intron_variant, non_coding_transcript_variant
DNMBP	XM_011539559.3	c.2189A>G	p.Glu730Gly	missense_variant	5/18
DNMBP	XM_047424910.1	c.2189A>G	p.Glu730Gly	missense_variant	5/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNMBP	ENST00000324109.9	c.2189A>G	p.Glu730Gly	missense_variant	4/17	1	NM_015221.4	P1
DNMBP-AS1	ENST00000661385.1	n.223-1197T>C		intron_variant, non_coding_transcript_variant
DNMBP-AS1	ENST00000434409.2	n.173-389T>C		intron_variant, non_coding_transcript_variant		2
DNMBP-AS1	ENST00000661150.1	n.177-1504T>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 23, 2023

The c.2189A>G (p.E730G) alteration is located in exon 4 (coding exon 3) of the DNMBP gene. This alteration results from a A to G substitution at nucleotide position 2189, causing the glutamic acid (E) at amino acid position 730 to be replaced by a glycine (G). 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	0.078
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	T
Eigen	Benign	-0.026
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	M
MutationTaster	Benign	0.99	D;D
PrimateAI	Benign	0.34	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.056
Sift	Benign	0.059	T
Sift4G	Benign	0.12	T
Polyphen		0.016	B
Vest4		0.10
MutPred		0.21		Loss of stability (P = 0.0464);
MVP		0.54
MPC		0.19
ClinPred		0.85	D
GERP RS		4.5
Varity_R		0.15
gMVP		0.24

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-101715042;