12-31387716-T-C

Position:

• chr12-31387716-T-C

Variant summary

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

The NM_144973.4(DENND5B):​c.3712A>G​(p.Ser1238Gly) 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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DENND5B NM_144973.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.50

Genes affected

DENND5B (HGNC:28338): (DENN domain containing 5B) Enables guanyl-nucleotide exchange factor activity. Predicted to be involved in positive regulation of triglyceride transport and regulation of catalytic activity. Predicted to be located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

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=0.040480733).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DENND5B	NM_144973.4	c.3712A>G	p.Ser1238Gly	missense_variant	21/21	ENST00000389082.10	NP_659410.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DENND5B	ENST00000389082.10	c.3712A>G	p.Ser1238Gly	missense_variant	21/21	5	NM_144973.4	ENSP00000373734.5
DENND5B	ENST00000536562.5	c.3817A>G	p.Ser1273Gly	missense_variant	23/23	2		ENSP00000444889.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Nov 06, 2023

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; Variants in candidate genes are classified as variants of uncertain significance in accordance with ACMG guidelines (PMID: 25741868) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.055
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.017	T;T
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.17
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.84	T;T
M_CAP	Benign	0.0038	T
MetaRNN	Benign	0.040	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.81	N;.
PrimateAI	Uncertain	0.48	T
PROVEAN	Benign	-1.6	N;N
REVEL	Benign	0.039
Sift	Benign	0.39	T;T
Sift4G	Benign	0.40	T;T
Polyphen		0.0	B;B
Vest4		0.053
MutPred		0.27		.;Loss of loop (P = 0.0512);
MVP		0.14
MPC		0.49
ClinPred		0.34	T
GERP RS		3.9
Varity_R		0.055
gMVP		0.083

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: chr12-31540650;