chr10-99880120-A-C

Position:

• chr10-99880120-A-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_015221.4(DNMBP):​c.4239T>G​(p.Cys1413Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.365 in 1,613,876 control chromosomes in the GnomAD database, including 110,283 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.31 (7972 hom., cov: 32)
  • Exomes 𝑓: 0.37 (102311 hom.)
• Consequence: DNMBP NM_015221.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.788

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=6.417036E-4).
• BP6: Variant 10-99880120-A-C is Benign according to our data. Variant chr10-99880120-A-C is described in ClinVar as [Benign]. Clinvar id is 1255520.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.373 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNMBP	NM_015221.4	c.4239T>G	p.Cys1413Trp	missense_variant	16/17	ENST00000324109.9	NP_056036.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNMBP	ENST00000324109.9	c.4239T>G	p.Cys1413Trp	missense_variant	16/17	1	NM_015221.4	ENSP00000315659	P1
DNMBP	ENST00000543621.6	c.2103T>G	p.Cys701Trp	missense_variant	13/14	1		ENSP00000443657
DNMBP	ENST00000636706.1	c.3135T>G	p.Cys1045Trp	missense_variant	13/14	2		ENSP00000489875

Frequencies

GnomAD3 genomes AF: 0.311 AC: 47247 AN: 151908 Hom.: 7979 Cov.: 32

Gnomad AFR AF: 0.186

Gnomad AMI AF: 0.515

Gnomad AMR AF: 0.334

Gnomad ASJ AF: 0.332

Gnomad EAS AF: 0.233

Gnomad SAS AF: 0.350

Gnomad FIN AF: 0.337

Gnomad MID AF: 0.320

Gnomad NFE AF: 0.376

Gnomad OTH AF: 0.334

GnomAD3 exomes AF: 0.344 AC: 86417 AN: 251480 Hom.: 15270 AF XY: 0.349 AC XY: 47408 AN XY: 135910

Gnomad AFR exome AF: 0.184

Gnomad AMR exome AF: 0.345

Gnomad ASJ exome AF: 0.330

Gnomad EAS exome AF: 0.237

Gnomad SAS exome AF: 0.355

Gnomad FIN exome AF: 0.342

Gnomad NFE exome AF: 0.381

Gnomad OTH exome AF: 0.362

GnomAD4 exome AF: 0.371 AC: 542161 AN: 1461850 Hom.: 102311 Cov.: 58 AF XY: 0.371 AC XY: 269942 AN XY: 727230

Gnomad4 AFR exome AF: 0.180

Gnomad4 AMR exome AF: 0.344

Gnomad4 ASJ exome AF: 0.336

Gnomad4 EAS exome AF: 0.235

Gnomad4 SAS exome AF: 0.357

Gnomad4 FIN exome AF: 0.346

Gnomad4 NFE exome AF: 0.387

Gnomad4 OTH exome AF: 0.356

GnomAD4 genome AF: 0.311 AC: 47256 AN: 152026 Hom.: 7972 Cov.: 32 AF XY: 0.311 AC XY: 23103 AN XY: 74324

Gnomad4 AFR AF: 0.186

Gnomad4 AMR AF: 0.334

Gnomad4 ASJ AF: 0.332

Gnomad4 EAS AF: 0.232

Gnomad4 SAS AF: 0.350

Gnomad4 FIN AF: 0.337

Gnomad4 NFE AF: 0.377

Gnomad4 OTH AF: 0.334

Alfa AF: 0.361 Hom.: 24826

Bravo AF: 0.305

TwinsUK AF: 0.398 AC: 1477

ALSPAC AF: 0.386 AC: 1486

ESP6500AA AF: 0.188 AC: 827

ESP6500EA AF: 0.380 AC: 3271

ExAC AF: 0.344 AC: 41783

Asia WGS AF: 0.283 AC: 985 AN: 3478

EpiCase AF: 0.375

EpiControl AF: 0.379

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

DNMBP-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 21, 2019

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

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	4.8
DANN	Benign	0.64
DEOGEN2	Benign	0.024	.;.;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.28	T;T;T
MetaRNN	Benign	0.00064	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.90	.;.;L
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.6	.;.;N
REVEL	Benign	0.058
Sift	Benign	0.18	.;.;T
Sift4G	Benign	0.18	.;.;T
Polyphen		0.33	.;.;B
Vest4		0.13
MPC		0.19
ClinPred		0.0031	T
GERP RS		0.60
Varity_R		0.030
gMVP		0.17

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

Publications

LitVar

Other links and lift over

dbSNP: rs11190305; hg19: chr10-101639877; COSMIC: COSV60621666;