Variant 7-140522017-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_015689.5(DENND2A):c.2749T>C(p.Phe917Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000109 in 1,461,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

DENND2A
NM_015689.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.81

Variant links:

Genes affected

DENND2A (HGNC:22212): (DENN domain containing 2A) Enables guanyl-nucleotide exchange factor activity. Involved in retrograde transport, endosome to Golgi. Located in actin cytoskeleton. [provided by Alliance of Genome Resources, Apr 2022]

DENND2A links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.858

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DENND2A	NM_015689.5 link	c.2749T>C	p.Phe917Leu	missense_variant	18/20	ENST00000496613.6	NP_056504.3	Q9ULE3-1A2RUF6
DENND2A	NM_001318052.2 link	c.2749T>C	p.Phe917Leu	missense_variant	17/19		NP_001304981.1	Q9ULE3-1
DENND2A	NM_001362678.2 link	c.2749T>C	p.Phe917Leu	missense_variant	18/20		NP_001349607.1
DENND2A	NR_134477.1 link	n.2836T>C		non_coding_transcript_exon_variant	16/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DENND2A	ENST00000496613.6 link	c.2749T>C	p.Phe917Leu	missense_variant	18/20	2	NM_015689.5	ENSP00000419654.1		Q9ULE3-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000802

AC:

AN:

249486

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

135382

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000109

AC:

AN:

1461880

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000117

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000826

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 27, 2023

The c.2749T>C (p.F917L) alteration is located in exon 16 (coding exon 16) of the DENND2A gene. This alteration results from a T to C substitution at nucleotide position 2749, causing the phenylalanine (F) at amino acid position 917 to be replaced by a leucine (L). 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

0.98

BayesDel_addAF

Uncertain

0.058

BayesDel_noAF

Uncertain

-0.060

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.23

T;T;T

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.89

.;D;.

M_CAP

Benign

0.024

MetaRNN

Pathogenic

0.86

D;D;D

MetaSVM

Benign

-0.71

MutationAssessor

Uncertain

2.6

M;M;M

PrimateAI

Pathogenic

0.82

PROVEAN

Uncertain

-4.3

D;D;D

REVEL

Uncertain

0.33

Sift

Benign

0.051

T;T;T

Sift4G

Benign

0.14

T;T;T

Polyphen

0.76

P;P;P

Vest4

0.84

MutPred

0.72

Gain of phosphorylation at S920 (P = 0.1306);Gain of phosphorylation at S920 (P = 0.1306);Gain of phosphorylation at S920 (P = 0.1306);

MVP

0.53

MPC

0.75

ClinPred

0.97

GERP RS

5.3

Varity_R

0.35

gMVP

0.60

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

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