12-31389424-A-C

Position:

• chr12-31389424-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_144973.4(DENND5B):​c.3541T>G​(p.Ser1181Ala) 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. 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: 1.98

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07806775).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DENND5B	NM_144973.4	c.3541T>G	p.Ser1181Ala	missense_variant	20/21	ENST00000389082.10	NP_659410.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DENND5B	ENST00000389082.10	c.3541T>G	p.Ser1181Ala	missense_variant	20/21	5	NM_144973.4	ENSP00000373734.5
DENND5B	ENST00000536562.5	c.3646T>G	p.Ser1216Ala	missense_variant	22/23	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 specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 06, 2024

The c.3541T>G (p.S1181A) alteration is located in exon 20 (coding exon 20) of the DENND5B gene. This alteration results from a T to G substitution at nucleotide position 3541, causing the serine (S) at amino acid position 1181 to be replaced by an alanine (A). 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	0.067
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	17
DANN	Benign	0.90
DEOGEN2	Benign	0.0048	T;T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.13
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.79	T;T
M_CAP	Benign	0.0069	T
MetaRNN	Benign	0.078	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.49	N;.
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.35	N;N
REVEL	Benign	0.088
Sift	Benign	0.78	T;T
Sift4G	Benign	0.84	T;T
Polyphen		0.016	B;B
Vest4		0.16
MutPred		0.30		.;Gain of catalytic residue at K1218 (P = 0);
MVP		0.36
MPC		0.45
ClinPred		0.17	T
GERP RS		4.6
Varity_R		0.080
gMVP		0.18

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: chr12-31542358;