3-57633276-T-C

Position:

• chr3-57633276-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_152678.3(DENND6A):​c.1342A>G​(p.Ile448Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DENND6A NM_152678.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.59

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.394149).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DENND6A	NM_152678.3	c.1342A>G	p.Ile448Val	missense_variant	15/20	ENST00000311128.10	NP_689891.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DENND6A	ENST00000311128.10	c.1342A>G	p.Ile448Val	missense_variant	15/20	1	NM_152678.3	ENSP00000311401.5
DENND6A	ENST00000471531.1	c.55A>G	p.Ile19Val	missense_variant	1/4	3		ENSP00000419570.1
DENND6A-AS1	ENST00000470427.1	n.69+4398T>C		intron_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 07, 2022

The c.1342A>G (p.I448V) alteration is located in exon 15 (coding exon 15) of the DENND6A gene. This alteration results from a A to G substitution at nucleotide position 1342, causing the isoleucine (I) at amino acid position 448 to be replaced by a valine (V). 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	Benign	0.16
BayesDel_addAF	Uncertain	0.049	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.056	T
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.0038	T
MetaRNN	Benign	0.39	T
MetaSVM	Benign	-0.54	T
MutationAssessor	Uncertain	2.6	M
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-0.47	N
REVEL	Benign	0.23
Sift	Uncertain	0.018	D
Sift4G	Uncertain	0.030	D
Polyphen		0.86	P
Vest4		0.41
MutPred		0.70		Loss of catalytic residue at P450 (P = 0.0271);
MVP		0.37
MPC		0.38
ClinPred		0.89	D
GERP RS		5.5
Varity_R		0.18
gMVP		0.39

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-57619003;