10-99879925-G-A

Variant names:

• chr10-99879925-G-A
• rs61757225
• NM_015221.4:c.4434C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BA1

The NM_015221.4(DNMBP):​c.4434C>T​(p.Ser1478Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0363 in 1,614,182 control chromosomes in the GnomAD database, including 1,351 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.032 (82 hom., cov: 32)
  • Exomes 𝑓: 0.037 (1269 hom.)
• Consequence: DNMBP NM_015221.4 synonymous
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -1.50
• Publications: 6 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=-0.73).
• BP6: Variant 10-99879925-G-A is Benign according to our data. Variant chr10-99879925-G-A is described in ClinVar as Benign. ClinVar VariationId is 3060443.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=-1.5 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0814 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNMBP	NM_015221.4	MANE Select	c.4434C>T	p.Ser1478Ser	synonymous	Exon 16 of 17	NP_056036.1	Q6XZF7-1
	DNMBP	NM_001441287.1		c.4434C>T	p.Ser1478Ser	synonymous	Exon 17 of 18	NP_001428216.1
	DNMBP	NM_001441288.1		c.4305C>T	p.Ser1435Ser	synonymous	Exon 15 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.4434C>T	p.Ser1478Ser	synonymous	Exon 16 of 17	ENSP00000315659.4	Q6XZF7-1
	DNMBP	ENST00000543621.6	TSL:1	c.2298C>T	p.Ser766Ser	synonymous	Exon 13 of 14	ENSP00000443657.2	A0A1C7CYY6
	DNMBP	ENST00000856964.1		c.4434C>T	p.Ser1478Ser	synonymous	Exon 17 of 18	ENSP00000527023.1

Frequencies

GnomAD3 genomes AF: 0.0317 AC: 4831 AN: 152170 Hom.: 80 Cov.: 32

Gnomad AFR AF: 0.0270

Gnomad AMI AF: 0.0197

Gnomad AMR AF: 0.0280

Gnomad ASJ AF: 0.0236

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.0878

Gnomad FIN AF: 0.0244

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0357

Gnomad OTH AF: 0.0287

GnomAD2 exomes AF: 0.0354 AC: 8892 AN: 251482 AF XY: 0.0390

Gnomad AFR exome AF: 0.0282

Gnomad AMR exome AF: 0.0157

Gnomad ASJ exome AF: 0.0221

Gnomad EAS exome AF: 0.000870

Gnomad FIN exome AF: 0.0277

Gnomad NFE exome AF: 0.0355

Gnomad OTH exome AF: 0.0314

GnomAD4 exome AF: 0.0368 AC: 53824 AN: 1461894 Hom.: 1269 Cov.: 31 AF XY: 0.0385 AC XY: 27978 AN XY: 727248

African (AFR) AF: 0.0259 AC: 866 AN: 33480

American (AMR) AF: 0.0163 AC: 728 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0236 AC: 617 AN: 26136

East Asian (EAS) AF: 0.000655 AC: 26 AN: 39700

South Asian (SAS) AF: 0.0885 AC: 7636 AN: 86258

European-Finnish (FIN) AF: 0.0265 AC: 1415 AN: 53420

Middle Eastern (MID) AF: 0.0244 AC: 141 AN: 5768

European-Non Finnish (NFE) AF: 0.0362 AC: 40246 AN: 1112012

Other (OTH) AF: 0.0356 AC: 2149 AN: 60396

GnomAD4 genome AF: 0.0318 AC: 4844 AN: 152288 Hom.: 82 Cov.: 32 AF XY: 0.0317 AC XY: 2360 AN XY: 74472

African (AFR) AF: 0.0270 AC: 1120 AN: 41554

American (AMR) AF: 0.0279 AC: 427 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0236 AC: 82 AN: 3470

East Asian (EAS) AF: 0.00154 AC: 8 AN: 5192

South Asian (SAS) AF: 0.0883 AC: 426 AN: 4826

European-Finnish (FIN) AF: 0.0244 AC: 259 AN: 10610

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0358 AC: 2432 AN: 68026

Other (OTH) AF: 0.0326 AC: 69 AN: 2114

Alfa AF: 0.0331 Hom.: 51

Bravo AF: 0.0296

Asia WGS AF: 0.0660 AC: 230 AN: 3478

EpiCase AF: 0.0364

EpiControl AF: 0.0361

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	-0.73
CADD	Benign	1.6
DANN	Benign	0.49
PhyloP100		-1.5
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs61757225; hg19: chr10-101639682; COSMIC: COSV60625179;