10-99877332-T-C

Variant names:

• chr10-99877332-T-C
• rs139264891
• NM_015221.4:c.4553A>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_015221.4(DNMBP):​c.4553A>G​(p.Tyr1518Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000446 in 1,609,374 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00040 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00045 (8 hom.)
• Consequence: DNMBP NM_015221.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.89
• Publications: 4 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.21488997).
• BS2: High Homozygotes in GnomAdExome4 at 8 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.4553A>G	p.Tyr1518Cys	missense	Exon 17 of 17	NP_056036.1	Q6XZF7-1
	DNMBP	NM_001441287.1		c.4553A>G	p.Tyr1518Cys	missense	Exon 18 of 18	NP_001428216.1
	DNMBP	NM_001441288.1		c.4424A>G	p.Tyr1475Cys	missense	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.4553A>G	p.Tyr1518Cys	missense	Exon 17 of 17	ENSP00000315659.4	Q6XZF7-1
	DNMBP	ENST00000543621.6	TSL:1	c.2417A>G	p.Tyr806Cys	missense	Exon 14 of 14	ENSP00000443657.2	A0A1C7CYY6
	DNMBP	ENST00000856964.1		c.4553A>G	p.Tyr1518Cys	missense	Exon 18 of 18	ENSP00000527023.1

Frequencies

GnomAD3 genomes AF: 0.000402 AC: 61 AN: 151730 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000585

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.000379

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000574

Gnomad OTH AF: 0.000481

GnomAD2 exomes AF: 0.000669 AC: 165 AN: 246774 AF XY: 0.000742

Gnomad AFR exome AF: 0.0000619

Gnomad AMR exome AF: 0.000483

Gnomad ASJ exome AF: 0.000508

Gnomad EAS exome AF: 0.000386

Gnomad FIN exome AF: 0.000279

Gnomad NFE exome AF: 0.000615

Gnomad OTH exome AF: 0.00167

GnomAD4 exome AF: 0.000450 AC: 656 AN: 1457524 Hom.: 8 Cov.: 31 AF XY: 0.000497 AC XY: 360 AN XY: 724952

African (AFR) AF: 0.00 AC: 0 AN: 33354

American (AMR) AF: 0.000386 AC: 17 AN: 44020

Ashkenazi Jewish (ASJ) AF: 0.000270 AC: 7 AN: 25948

East Asian (EAS) AF: 0.000203 AC: 8 AN: 39482

South Asian (SAS) AF: 0.00197 AC: 168 AN: 85432

European-Finnish (FIN) AF: 0.000506 AC: 27 AN: 53354

Middle Eastern (MID) AF: 0.00331 AC: 19 AN: 5746

European-Non Finnish (NFE) AF: 0.000339 AC: 376 AN: 1109962

Other (OTH) AF: 0.000565 AC: 34 AN: 60226

GnomAD4 genome AF: 0.000402 AC: 61 AN: 151850 Hom.: 0 Cov.: 32 AF XY: 0.000391 AC XY: 29 AN XY: 74198

African (AFR) AF: 0.00 AC: 0 AN: 41388

American (AMR) AF: 0.000131 AC: 2 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3468

East Asian (EAS) AF: 0.000586 AC: 3 AN: 5116

South Asian (SAS) AF: 0.00228 AC: 11 AN: 4816

European-Finnish (FIN) AF: 0.000379 AC: 4 AN: 10552

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

European-Non Finnish (NFE) AF: 0.000574 AC: 39 AN: 67962

Other (OTH) AF: 0.000476 AC: 1 AN: 2100

Alfa AF: 0.000595 Hom.: 0

Bravo AF: 0.000378

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000717 AC: 87

EpiCase AF: 0.00110

EpiControl AF: 0.000834

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Benign	-0.010	T
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	T
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.30	T
MutationAssessor	Benign	0.64	N
PhyloP100		4.9
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-6.7	D
REVEL	Pathogenic	0.69
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.78
MVP		0.87
MPC		0.70
ClinPred		0.10	T
GERP RS		5.4
Varity_R		0.86
gMVP		0.71
Mutation Taster		=81/19	polymorphism

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: rs139264891; hg19: chr10-101637089;