8-141136713-C-T

Position:

• chr8-141136713-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001352890.3(DENND3):​c.307C>T​(p.Pro103Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DENND3 NM_001352890.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.454

Genes affected

DENND3 (HGNC:29134): (DENN domain containing 3) Enables guanyl-nucleotide exchange factor activity. Predicted to be involved in cellular protein catabolic process; endosome to lysosome transport; and regulation of Rab protein signal transduction. Predicted to be located in cytosol. Predicted to be active in cytoplasmic vesicle. [provided by Alliance of Genome Resources, Apr 2022]

DENND3 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03935349).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DENND3	NM_001352890.3	c.307C>T	p.Pro103Ser	missense_variant	2/23	ENST00000519811.6	NP_001339819.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DENND3	ENST00000519811.6	c.307C>T	p.Pro103Ser	missense_variant	2/23	5	NM_001352890.3	ENSP00000428714.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 19, 2024

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	0.13
DANN	Benign	0.32
DEOGEN2	Benign	0.0098	T;.;T;.;T;T;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.048	N
LIST_S2	Benign	0.60	T;T;T;T;T;T;T
M_CAP	Benign	0.0070	T
MetaRNN	Benign	0.039	T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.46	.;.;N;.;.;.;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.17	N;N;N;N;N;N;N
REVEL	Benign	0.021
Sift	Benign	0.92	T;T;T;T;T;T;T
Sift4G	Benign	0.97	T;T;T;T;T;T;T
Polyphen		0.0, 0.0020	.;B;B;B;B;.;.
Vest4		0.043, 0.055, 0.079, 0.064
MutPred		0.24		.;Gain of phosphorylation at P103 (P = 0.0101);.;Gain of phosphorylation at P103 (P = 0.0101);Gain of phosphorylation at P103 (P = 0.0101);Gain of phosphorylation at P103 (P = 0.0101);.;
MVP		0.055
MPC		0.43
ClinPred		0.017	T
GERP RS		0.41
Varity_R		0.018
gMVP		0.22

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: chr8-142146812;