11-8699390-A-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

The NM_213618.2(DENND2B):c.2721T>A(p.Ser907Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000079 in 1,594,282 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000081 ( 0 hom. )

Consequence

DENND2B
NM_213618.2 missense, splice_region

Scores

Splicing: ADA: 0.00005098

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.47

Variant links:

Genes affected

DENND2B (HGNC:11350): (DENN domain containing 2B) This gene was identified by its ability to suppress the tumorigenicity of Hela cells in nude mice. The protein encoded by this gene contains a C-terminal region that shares similarity with the Rab 3 family of small GTP binding proteins. This protein preferentially binds to the SH3 domain of c-Abl kinase, and acts as a regulator of MAPK1/ERK2 kinase, which may contribute to its ability to reduce the tumorigenic phenotype in cells. Three alternatively spliced transcript variants of this gene encoding distinct isoforms are identified. [provided by RefSeq, Jul 2008]

DENND2B links:

RPL27A (HGNC:10329): (ribosomal protein L27a) Ribosomes, the organelles that catalyze protein synthesis, consist of a small 40S subunit and a large 60S subunit. Together these subunits are composed of 4 RNA species and approximately 80 structurally distinct proteins. This gene encodes a ribosomal protein that is a component of the 60S subunit. The protein belongs to the L15P family of ribosomal proteins. It is located in the cytoplasm. Variable expression of this gene in colorectal cancers compared to adjacent normal tissues has been observed, although no correlation between the level of expression and the severity of the disease has been found. As is typical for genes encoding ribosomal proteins, multiple processed pseudogenes derived from this gene are dispersed through the genome. [provided by RefSeq, Jul 2008]

RPL27A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.75

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DENND2B	NM_213618.2 link	c.2721T>A	p.Ser907Arg	missense_variant, splice_region_variant	Exon 15 of 20	ENST00000313726.11	NP_998783.1	P78524-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DENND2B	ENST00000313726.11 link	c.2721T>A	p.Ser907Arg	missense_variant, splice_region_variant	Exon 15 of 20	1	NM_213618.2	ENSP00000319678.6		P78524-1

Frequencies

GnomAD3 genomes

AF:

0.0000591

AC:

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000442

AC:

AN:

226268

AF XY:

0.0000325

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000184

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000379

Gnomad OTH exome

AF:

0.000183

GnomAD4 exome

AF:

0.0000811

AC:

117

AN:

1442110

Hom.:

Cov.:

AF XY:

0.0000766

AC XY:

AN XY:

717586

show subpopulations

Gnomad4 AFR exome

AF:

0.00

AC:

AN:

32004

Gnomad4 AMR exome

AF:

0.000161

AC:

AN:

37294

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

25106

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

39404

Gnomad4 SAS exome

AF:

0.00

AC:

AN:

83356

Gnomad4 FIN exome

AF:

0.00

AC:

AN:

53114

Gnomad4 NFE exome

AF:

0.0000921

AC:

102

AN:

1106926

Gnomad4 Remaining exome

AF:

0.000151

AC:

AN:

59496

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000591

AC:

AN:

152172

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.0000241

AC:

0.0000241278

AN:

0.0000241278

Gnomad4 AMR

AF:

0.000327

AC:

0.000327097

AN:

0.000327097

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.00

AC:

AN:

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.0000441

AC:

0.0000441125

AN:

0.0000441125

Gnomad4 OTH

AF:

0.00

AC:

AN:

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.000193

ExAC

AF:

0.0000412

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 19, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.2721T>A (p.S907R) alteration is located in exon 18 (coding exon 14) of the ST5 gene. This alteration results from a T to A substitution at nucleotide position 2721, causing the serine (S) at amino acid position 907 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.91

BayesDel_addAF

Benign

-0.012

BayesDel_noAF

Uncertain

0.0

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.25

.;T;T;.;T;T;.

Eigen

Benign

-0.056

Eigen_PC

Benign

-0.095

FATHMM_MKL

Uncertain

0.76

LIST_S2

Uncertain

0.94

.;.;D;D;D;D;D

M_CAP

Benign

0.061

MetaRNN

Pathogenic

0.75

D;D;D;D;D;D;D

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.2

.;M;M;.;.;.;.

PrimateAI

Pathogenic

0.84

PROVEAN

Uncertain

-4.0

D;D;D;D;D;D;D

REVEL

Uncertain

0.40

Sift

Uncertain

0.022

D;D;D;T;D;T;D

Sift4G

Uncertain

0.020

D;D;D;D;D;D;D

Polyphen

0.65

P;P;P;.;P;.;P

Vest4

0.91

MutPred

0.55

.;Gain of MoRF binding (P = 0.0534);Gain of MoRF binding (P = 0.0534);.;.;.;.;

MVP

0.87

MPC

1.6

ClinPred

0.50

GERP RS

-0.68

Varity_R

0.38

gMVP

0.93

Mutation Taster

=33/67

disease causing

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000051

dbscSNV1_RF

Benign

0.15

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over