10-99912584-A-G

Variant names:

• chr10-99912584-A-G
• rs10883421
• NM_015221.4:c.2261-3438T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_015221.4(DNMBP):​c.2261-3438T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.442 in 152,008 control chromosomes in the GnomAD database, including 15,081 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.44 (15081 hom., cov: 32)
• Consequence: DNMBP NM_015221.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.599
• Publications: 4 publications found

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 Gene-Disease associations (from GenCC):

• cataract 48

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• total early-onset cataract

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.454 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015221.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNMBP	NM_015221.4	MANE Select	c.2261-3438T>C		intron	N/A	NP_056036.1
	DNMBP	NM_001441287.1		c.2261-3438T>C		intron	N/A	NP_001428216.1
	DNMBP	NM_001441288.1		c.2261-3438T>C		intron	N/A	NP_001428217.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNMBP	ENST00000324109.9	TSL:1 MANE Select	c.2261-3438T>C		intron	N/A	ENSP00000315659.4
	DNMBP	ENST00000543621.6	TSL:1	c.124+1369T>C		intron	N/A	ENSP00000443657.2
	DNMBP	ENST00000636706.1	TSL:2	c.1157-3438T>C		intron	N/A	ENSP00000489875.1

Frequencies

GnomAD3 genomes AF: 0.442 AC: 67134 AN: 151890 Hom.: 15074 Cov.: 32

Gnomad AFR AF: 0.456

Gnomad AMI AF: 0.542

Gnomad AMR AF: 0.433

Gnomad ASJ AF: 0.409

Gnomad EAS AF: 0.232

Gnomad SAS AF: 0.455

Gnomad FIN AF: 0.396

Gnomad MID AF: 0.383

Gnomad NFE AF: 0.458

Gnomad OTH AF: 0.448

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.442 AC: 67186 AN: 152008 Hom.: 15081 Cov.: 32 AF XY: 0.439 AC XY: 32609 AN XY: 74268

African (AFR) AF: 0.455 AC: 18879 AN: 41450

American (AMR) AF: 0.433 AC: 6608 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.409 AC: 1419 AN: 3466

East Asian (EAS) AF: 0.231 AC: 1194 AN: 5166

South Asian (SAS) AF: 0.454 AC: 2186 AN: 4814

European-Finnish (FIN) AF: 0.396 AC: 4180 AN: 10546

Middle Eastern (MID) AF: 0.384 AC: 113 AN: 294

European-Non Finnish (NFE) AF: 0.458 AC: 31160 AN: 67986

Other (OTH) AF: 0.451 AC: 953 AN: 2112

Alfa AF: 0.450 Hom.: 6271

Bravo AF: 0.445

Asia WGS AF: 0.370 AC: 1287 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	5.8
DANN	Benign	0.59
PhyloP100		0.60
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs10883421; hg19: chr10-101672341;