3-57630479-C-T

Variant summary

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

The NM_152678.3(DENND6A):​c.1562G>A​(p.Arg521Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000138 in 1,594,696 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: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

DENND6A
NM_152678.3 missense

Scores

11
5
3

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.86
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, 0.912

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
DENND6ANM_152678.3 linkc.1562G>A p.Arg521Gln missense_variant 18/20 ENST00000311128.10 NP_689891.1 Q8IWF6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
DENND6AENST00000311128.10 linkc.1562G>A p.Arg521Gln missense_variant 18/201 NM_152678.3 ENSP00000311401.5 Q8IWF6
DENND6AENST00000471531.1 linkc.275G>A p.Arg92Gln missense_variant 4/43 ENSP00000419570.1 H7C5D0
DENND6A-AS1ENST00000470427.1 linkn.69+1601C>T intron_variant 2

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152114
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.0000944
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000258
AC:
6
AN:
232738
Hom.:
0
AF XY:
0.0000158
AC XY:
2
AN XY:
126248
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000178
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0000468
Gnomad NFE exome
AF:
0.0000183
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000139
AC:
20
AN:
1442582
Hom.:
0
Cov.:
30
AF XY:
0.0000125
AC XY:
9
AN XY:
717404
show subpopulations
Gnomad4 AFR exome
AF:
0.0000313
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000101
Gnomad4 SAS exome
AF:
0.0000122
Gnomad4 FIN exome
AF:
0.0000563
Gnomad4 NFE exome
AF:
0.00000993
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152114
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74284
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.0000944
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000189
ExAC
AF:
0.0000165
AC:
2

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 GeneticsOct 25, 2024The c.1562G>A (p.R521Q) alteration is located in exon 18 (coding exon 18) of the DENND6A gene. This alteration results from a G to A substitution at nucleotide position 1562, causing the arginine (R) at amino acid position 521 to be replaced by a glutamine (Q). 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
0.70
BayesDel_addAF
Pathogenic
0.23
D
BayesDel_noAF
Pathogenic
0.37
CADD
Pathogenic
31
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.24
T
Eigen
Pathogenic
0.84
Eigen_PC
Pathogenic
0.81
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Pathogenic
0.99
D
M_CAP
Benign
0.017
T
MetaRNN
Pathogenic
0.91
D
MetaSVM
Uncertain
-0.026
T
MutationAssessor
Pathogenic
3.2
M
PrimateAI
Uncertain
0.70
T
PROVEAN
Uncertain
-3.6
D
REVEL
Uncertain
0.61
Sift
Pathogenic
0.0
D
Sift4G
Uncertain
0.0050
D
Polyphen
1.0
D
Vest4
0.71
MutPred
0.82
Loss of MoRF binding (P = 0.0487);
MVP
0.49
MPC
1.3
ClinPred
0.95
D
GERP RS
5.7
Varity_R
0.65
gMVP
0.83

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.080
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: rs781356154; hg19: chr3-57616206; API