NM_015221.4:c.4725G>A

Variant names:

• chr10-99877160-C-T
• rs11190304
• NM_015221.4:c.4725G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_015221.4(DNMBP):​c.4725G>A​(p.Glu1575Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0225 in 1,609,802 control chromosomes in the GnomAD database, including 435 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.017 (23 hom., cov: 32)
  • Exomes 𝑓: 0.023 (412 hom.)
• Consequence: DNMBP NM_015221.4 synonymous
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.350
• Publications: 5 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 10-99877160-C-T is Benign according to our data. Variant chr10-99877160-C-T is described in ClinVar as Benign. ClinVar VariationId is 3038273.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=0.35 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0172 (2620/152240) while in subpopulation NFE AF = 0.0248 (1685/68020). AF 95% confidence interval is 0.0238. There are 23 homozygotes in GnomAd4. There are 1258 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 23 AD,AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNMBP	NM_015221.4	MANE Select	c.4725G>A	p.Glu1575Glu	synonymous	Exon 17 of 17	NP_056036.1	Q6XZF7-1
	DNMBP	NM_001441287.1		c.4725G>A	p.Glu1575Glu	synonymous	Exon 18 of 18	NP_001428216.1
	DNMBP	NM_001441288.1		c.4596G>A	p.Glu1532Glu	synonymous	Exon 16 of 16	NP_001428217.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNMBP	ENST00000324109.9	TSL:1 MANE Select	c.4725G>A	p.Glu1575Glu	synonymous	Exon 17 of 17	ENSP00000315659.4	Q6XZF7-1
	DNMBP	ENST00000543621.6	TSL:1	c.2589G>A	p.Glu863Glu	synonymous	Exon 14 of 14	ENSP00000443657.2	A0A1C7CYY6
	DNMBP	ENST00000856964.1		c.4725G>A	p.Glu1575Glu	synonymous	Exon 18 of 18	ENSP00000527023.1

Frequencies

GnomAD3 genomes AF: 0.0172 AC: 2623 AN: 152122 Hom.: 23 Cov.: 32

Gnomad AFR AF: 0.00418

Gnomad AMI AF: 0.0482

Gnomad AMR AF: 0.0136

Gnomad ASJ AF: 0.0245

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0104

Gnomad FIN AF: 0.0329

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0248

Gnomad OTH AF: 0.0110

GnomAD2 exomes AF: 0.0185 AC: 4529 AN: 245038 AF XY: 0.0185

Gnomad AFR exome AF: 0.00395

Gnomad AMR exome AF: 0.00654

Gnomad ASJ exome AF: 0.0292

Gnomad EAS exome AF: 0.0000563

Gnomad FIN exome AF: 0.0323

Gnomad NFE exome AF: 0.0255

Gnomad OTH exome AF: 0.0207

GnomAD4 exome AF: 0.0231 AC: 33664 AN: 1457562 Hom.: 412 Cov.: 31 AF XY: 0.0227 AC XY: 16446 AN XY: 724952

African (AFR) AF: 0.00354 AC: 118 AN: 33326

American (AMR) AF: 0.00760 AC: 335 AN: 44100

Ashkenazi Jewish (ASJ) AF: 0.0270 AC: 702 AN: 25994

East Asian (EAS) AF: 0.0000254 AC: 1 AN: 39322

South Asian (SAS) AF: 0.00939 AC: 802 AN: 85372

European-Finnish (FIN) AF: 0.0341 AC: 1818 AN: 53368

Middle Eastern (MID) AF: 0.0108 AC: 62 AN: 5758

European-Non Finnish (NFE) AF: 0.0258 AC: 28695 AN: 1110082

Other (OTH) AF: 0.0188 AC: 1131 AN: 60240

GnomAD4 genome AF: 0.0172 AC: 2620 AN: 152240 Hom.: 23 Cov.: 32 AF XY: 0.0169 AC XY: 1258 AN XY: 74432

African (AFR) AF: 0.00416 AC: 173 AN: 41540

American (AMR) AF: 0.0136 AC: 208 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0245 AC: 85 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5168

South Asian (SAS) AF: 0.00996 AC: 48 AN: 4818

European-Finnish (FIN) AF: 0.0329 AC: 349 AN: 10610

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0248 AC: 1685 AN: 68020

Other (OTH) AF: 0.0109 AC: 23 AN: 2114

Alfa AF: 0.0226 Hom.: 20

Bravo AF: 0.0154

Asia WGS AF: 0.00433 AC: 15 AN: 3478

EpiCase AF: 0.0236

EpiControl AF: 0.0235

ClinVar

ClinVar submissions

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	DNMBP-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	8.2
DANN	Benign	0.40
PhyloP100		0.35
Mutation Taster		=90/10	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: rs11190304; hg19: chr10-101636917;