10-99955291-C-T

Variant names:

• chr10-99955291-C-T
• NM_015221.4:c.2183G>A

Variant summary

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

The NM_015221.4(DNMBP):​c.2183G>A​(p.Arg728Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,882 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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: 0.0000014 (0 hom.)
• Consequence: DNMBP NM_015221.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.98

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=0.21079904).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNMBP	NM_015221.4	c.2183G>A	p.Arg728Lys	missense_variant	Exon 4 of 17	ENST00000324109.9	NP_056036.1
DNMBP	XM_011539559.3	c.2183G>A	p.Arg728Lys	missense_variant	Exon 5 of 18		XP_011537861.1
DNMBP	XM_047424910.1	c.2183G>A	p.Arg728Lys	missense_variant	Exon 5 of 18		XP_047280866.1
DNMBP-AS1	NR_024130.3	n.177-383C>T		intron_variant	Intron 2 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNMBP	ENST00000324109.9	c.2183G>A	p.Arg728Lys	missense_variant	Exon 4 of 17	1	NM_015221.4	ENSP00000315659.4
DNMBP-AS1	ENST00000434409.2	n.173-383C>T		intron_variant	Intron 2 of 4	2
DNMBP-AS1	ENST00000661150.1	n.177-1498C>T		intron_variant	Intron 2 of 2
DNMBP-AS1	ENST00000661385.1	n.223-1191C>T		intron_variant	Intron 2 of 3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461882 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727238

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 13, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2183G>A (p.R728K) alteration is located in exon 4 (coding exon 3) of the DNMBP gene. This alteration results from a G to A substitution at nucleotide position 2183, causing the arginine (R) at amino acid position 728 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	0.090
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.060	T
Eigen	Benign	0.070
Eigen_PC	Benign	-0.060
FATHMM_MKL	Benign	0.50	N
LIST_S2	Benign	0.60	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.9	M
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.052
Sift	Benign	0.10	T
Sift4G	Uncertain	0.029	D
Polyphen		0.99	D
Vest4		0.14
MutPred		0.32		Gain of ubiquitination at R728 (P = 0.0022);
MVP		0.58
MPC		0.34
ClinPred		0.57	D
GERP RS		1.7
Varity_R		0.12
gMVP		0.32

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: chr10-101715048;