NM_015221.4:c.4500G>A

Variant names:

• chr10-99879859-C-T
• rs77307082
• NM_015221.4:c.4500G>A

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.4500G>A​(p.Pro1500Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00472 in 1,614,234 control chromosomes in the GnomAD database, including 195 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0053 (23 hom., cov: 32)
  • Exomes 𝑓: 0.0047 (172 hom.)
• Consequence: DNMBP NM_015221.4 synonymous
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.485
• Publications: 3 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=-0.74).
• BP6: Variant 10-99879859-C-T is Benign according to our data. Variant chr10-99879859-C-T is described in ClinVar as Benign. ClinVar VariationId is 3033669.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=0.485 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0741 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.4500G>A	p.Pro1500Pro	synonymous	Exon 16 of 17	NP_056036.1	Q6XZF7-1
	DNMBP	NM_001441287.1		c.4500G>A	p.Pro1500Pro	synonymous	Exon 17 of 18	NP_001428216.1
	DNMBP	NM_001441288.1		c.4371G>A	p.Pro1457Pro	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.4500G>A	p.Pro1500Pro	synonymous	Exon 16 of 17	ENSP00000315659.4	Q6XZF7-1
	DNMBP	ENST00000543621.6	TSL:1	c.2364G>A	p.Pro788Pro	synonymous	Exon 13 of 14	ENSP00000443657.2	A0A1C7CYY6
	DNMBP	ENST00000856964.1		c.4500G>A	p.Pro1500Pro	synonymous	Exon 17 of 18	ENSP00000527023.1

Frequencies

GnomAD3 genomes AF: 0.00534 AC: 813 AN: 152222 Hom.: 24 Cov.: 32

Gnomad AFR AF: 0.000989

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00661

Gnomad ASJ AF: 0.00374

Gnomad EAS AF: 0.0809

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.00650

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00219

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.0116 AC: 2907 AN: 251072 AF XY: 0.00998

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.0220

Gnomad ASJ exome AF: 0.00506

Gnomad EAS exome AF: 0.0875

Gnomad FIN exome AF: 0.00730

Gnomad NFE exome AF: 0.00226

Gnomad OTH exome AF: 0.00440

GnomAD4 exome AF: 0.00465 AC: 6802 AN: 1461894 Hom.: 172 Cov.: 31 AF XY: 0.00447 AC XY: 3251 AN XY: 727248

African (AFR) AF: 0.000627 AC: 21 AN: 33480

American (AMR) AF: 0.0202 AC: 905 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00459 AC: 120 AN: 26136

East Asian (EAS) AF: 0.0811 AC: 3219 AN: 39700

South Asian (SAS) AF: 0.00179 AC: 154 AN: 86258

European-Finnish (FIN) AF: 0.00730 AC: 390 AN: 53420

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5768

European-Non Finnish (NFE) AF: 0.00150 AC: 1668 AN: 1112012

Other (OTH) AF: 0.00530 AC: 320 AN: 60396

GnomAD4 genome AF: 0.00532 AC: 810 AN: 152340 Hom.: 23 Cov.: 32 AF XY: 0.00593 AC XY: 442 AN XY: 74486

African (AFR) AF: 0.000986 AC: 41 AN: 41582

American (AMR) AF: 0.00654 AC: 100 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00374 AC: 13 AN: 3472

East Asian (EAS) AF: 0.0805 AC: 417 AN: 5182

South Asian (SAS) AF: 0.00290 AC: 14 AN: 4826

European-Finnish (FIN) AF: 0.00650 AC: 69 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00219 AC: 149 AN: 68040

Other (OTH) AF: 0.00331 AC: 7 AN: 2114

Alfa AF: 0.00293 Hom.: 4

Bravo AF: 0.00601

Asia WGS AF: 0.0330 AC: 113 AN: 3478

EpiCase AF: 0.00147

EpiControl AF: 0.000889

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	-0.74
CADD	Benign	6.6
DANN	Benign	0.34
PhyloP100		0.48
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: rs77307082; hg19: chr10-101639616; COSMIC: COSV60620544;