NM_015221.4:c.4320C>T

Variant names:

• chr10-99880039-G-A
• rs2255901
• NM_015221.4:c.4320C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_015221.4(DNMBP):​c.4320C>T​(p.Ser1440Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.509 in 1,613,852 control chromosomes in the GnomAD database, including 211,787 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.50 (19745 hom., cov: 32)
  • Exomes 𝑓: 0.51 (192042 hom.)
• Consequence: DNMBP NM_015221.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.845
• Publications: 15 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 10-99880039-G-A is Benign according to our data. Variant chr10-99880039-G-A is described in ClinVar as Benign. ClinVar VariationId is 1255519.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.534 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNMBP	NM_015221.4	c.4320C>T	p.Ser1440Ser	synonymous_variant	Exon 16 of 17	ENST00000324109.9	NP_056036.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNMBP	ENST00000324109.9	c.4320C>T	p.Ser1440Ser	synonymous_variant	Exon 16 of 17	1	NM_015221.4	ENSP00000315659.4
DNMBP	ENST00000543621.6	c.2184C>T	p.Ser728Ser	synonymous_variant	Exon 13 of 14	1		ENSP00000443657.2
DNMBP	ENST00000636706.1	c.3216C>T	p.Ser1072Ser	synonymous_variant	Exon 13 of 14	2		ENSP00000489875.1

Frequencies

GnomAD3 genomes AF: 0.505 AC: 76657 AN: 151900 Hom.: 19712 Cov.: 32

Gnomad AFR AF: 0.539

Gnomad AMI AF: 0.569

Gnomad AMR AF: 0.507

Gnomad ASJ AF: 0.490

Gnomad EAS AF: 0.255

Gnomad SAS AF: 0.489

Gnomad FIN AF: 0.419

Gnomad MID AF: 0.601

Gnomad NFE AF: 0.515

Gnomad OTH AF: 0.535

GnomAD2 exomes AF: 0.484 AC: 121671 AN: 251458 AF XY: 0.487

Gnomad AFR exome AF: 0.543

Gnomad AMR exome AF: 0.478

Gnomad ASJ exome AF: 0.488

Gnomad EAS exome AF: 0.258

Gnomad FIN exome AF: 0.424

Gnomad NFE exome AF: 0.520

Gnomad OTH exome AF: 0.509

GnomAD4 exome AF: 0.509 AC: 744586 AN: 1461834 Hom.: 192042 Cov.: 72 AF XY: 0.510 AC XY: 370684 AN XY: 727218

African (AFR) AF: 0.547 AC: 18308 AN: 33480

American (AMR) AF: 0.479 AC: 21413 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.497 AC: 12988 AN: 26134

East Asian (EAS) AF: 0.257 AC: 10210 AN: 39700

South Asian (SAS) AF: 0.496 AC: 42806 AN: 86258

European-Finnish (FIN) AF: 0.428 AC: 22853 AN: 53420

Middle Eastern (MID) AF: 0.530 AC: 3056 AN: 5768

European-Non Finnish (NFE) AF: 0.524 AC: 582496 AN: 1111954

Other (OTH) AF: 0.504 AC: 30456 AN: 60396

GnomAD4 genome AF: 0.505 AC: 76746 AN: 152018 Hom.: 19745 Cov.: 32 AF XY: 0.501 AC XY: 37216 AN XY: 74294

African (AFR) AF: 0.540 AC: 22383 AN: 41450

American (AMR) AF: 0.507 AC: 7732 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.490 AC: 1700 AN: 3468

East Asian (EAS) AF: 0.254 AC: 1314 AN: 5166

South Asian (SAS) AF: 0.489 AC: 2355 AN: 4814

European-Finnish (FIN) AF: 0.419 AC: 4427 AN: 10564

Middle Eastern (MID) AF: 0.605 AC: 178 AN: 294

European-Non Finnish (NFE) AF: 0.515 AC: 35003 AN: 67976

Other (OTH) AF: 0.538 AC: 1135 AN: 2110

Alfa AF: 0.516 Hom.: 10798

Bravo AF: 0.514

Asia WGS AF: 0.411 AC: 1429 AN: 3478

EpiCase AF: 0.529

EpiControl AF: 0.541

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

DNMBP-related disorder Benign:1

Oct 21, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Cataract 48 Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.51
DANN	Benign	0.41
PhyloP100		-0.84
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: rs2255901; hg19: chr10-101639796; COSMIC: COSV60621654;