3-57633269-G-A

Variant summary

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

The NM_152678.3(DENND6A):​c.1349C>T​(p.Pro450Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,068 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: 32)
Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

DENND6A
NM_152678.3 missense

Scores

14
3
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.49
Variant links:
Genes affected
DENND6A (HGNC:26635): (DENN domain containing 6A) Enables guanyl-nucleotide exchange factor activity. Involved in positive regulation of cell-cell adhesion mediated by cadherin. Located in recycling endosome. [provided by Alliance of Genome Resources, Apr 2022]
PDE12 (HGNC:25386): (phosphodiesterase 12) Enables 3'-5'-exoribonuclease activity. Involved in several processes, including RNA metabolic process; cellular response to cytokine stimulus; and regulation of mitochondrial mRNA stability. Located in mitochondrial matrix. [provided by Alliance of Genome Resources, Apr 2022]
DENND6A-AS1 (HGNC:41152): (DENND6A antisense RNA 1)

Genome browser will be placed here

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, 0.906

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
DENND6ANM_152678.3 linkc.1349C>T p.Pro450Leu missense_variant 15/20 ENST00000311128.10 NP_689891.1 Q8IWF6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
DENND6AENST00000311128.10 linkc.1349C>T p.Pro450Leu missense_variant 15/201 NM_152678.3 ENSP00000311401.5 Q8IWF6
DENND6AENST00000471531.1 linkc.62C>T p.Pro21Leu missense_variant 1/43 ENSP00000419570.1 H7C5D0
DENND6A-AS1ENST00000470427.1 linkn.69+4391G>A intron_variant 2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.85e-7
AC:
1
AN:
1459068
Hom.:
0
Cov.:
29
AF XY:
0.00000138
AC XY:
1
AN XY:
725950
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.01e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000378

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 submitterclinical testingAmbry GeneticsFeb 16, 2023The c.1349C>T (p.P450L) alteration is located in exon 15 (coding exon 15) of the DENND6A gene. This alteration results from a C to T substitution at nucleotide position 1349, causing the proline (P) at amino acid position 450 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
0.99
BayesDel_addAF
Pathogenic
0.50
D
BayesDel_noAF
Pathogenic
0.48
CADD
Pathogenic
32
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.51
D
Eigen
Pathogenic
1.0
Eigen_PC
Pathogenic
0.94
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Pathogenic
1.0
D
M_CAP
Benign
0.020
T
MetaRNN
Pathogenic
0.91
D
MetaSVM
Uncertain
0.29
D
MutationAssessor
Pathogenic
3.2
M
PrimateAI
Pathogenic
0.92
D
PROVEAN
Pathogenic
-9.4
D
REVEL
Pathogenic
0.94
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0
D
Polyphen
1.0
D
Vest4
0.93
MutPred
0.71
Gain of helix (P = 0.0034);
MVP
0.67
MPC
1.3
ClinPred
1.0
D
GERP RS
5.5
Varity_R
0.90
gMVP
0.88

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

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

Other links and lift over

dbSNP: rs2070724432; hg19: chr3-57618996; API