chr10-99880008-C-T

Variant names:

• chr10-99880008-C-T
• rs1235991239
• NM_015221.4:c.4351G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015221.4(DNMBP):​c.4351G>A​(p.Asp1451Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: DNMBP NM_015221.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.30
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.106809705).

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.4351G>A	p.Asp1451Asn	missense	Exon 16 of 17	NP_056036.1	Q6XZF7-1
	DNMBP	NM_001441287.1		c.4351G>A	p.Asp1451Asn	missense	Exon 17 of 18	NP_001428216.1
	DNMBP	NM_001441288.1		c.4222G>A	p.Asp1408Asn	missense	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.4351G>A	p.Asp1451Asn	missense	Exon 16 of 17	ENSP00000315659.4	Q6XZF7-1
	DNMBP	ENST00000543621.6	TSL:1	c.2215G>A	p.Asp739Asn	missense	Exon 13 of 14	ENSP00000443657.2	A0A1C7CYY6
	DNMBP	ENST00000856964.1		c.4351G>A	p.Asp1451Asn	missense	Exon 17 of 18	ENSP00000527023.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251476 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461892 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727248

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1112010

Other (OTH) AF: 0.0000166 AC: 1 AN: 60396

GnomAD4 genome Cov.: 32

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	Benign	0.090
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	15
DANN	Uncertain	0.98
DEOGEN2	Benign	0.020	T
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.71
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.0090	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		3.3
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.043
Sift	Uncertain	0.026	D
Sift4G	Uncertain	0.045	D
Polyphen		0.022	B
Vest4		0.36
MVP		0.47
MPC		0.20
ClinPred		0.16	T
GERP RS		4.5
Varity_R		0.051
gMVP		0.21
Mutation Taster		=86/14	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: rs1235991239; hg19: chr10-101639765;