chr12-31389328-T-A

Position:

• chr12-31389328-T-A

Variant summary

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

The NM_144973.4(DENND5B):​c.3637A>T​(p.Thr1213Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 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: 3.73

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=0.19764736).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DENND5B	NM_144973.4	c.3637A>T	p.Thr1213Ser	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.3637A>T	p.Thr1213Ser	missense_variant	20/21	5	NM_144973.4	ENSP00000373734.5
DENND5B	ENST00000536562.5	c.3742A>T	p.Thr1248Ser	missense_variant	22/23	2		ENSP00000444889.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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 01, 2023

The c.3637A>T (p.T1213S) alteration is located in exon 20 (coding exon 20) of the DENND5B gene. This alteration results from a A to T substitution at nucleotide position 3637, causing the threonine (T) at amino acid position 1213 to be replaced by a serine (S). 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	0.15
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0084	T;T
Eigen	Benign	-0.079
Eigen_PC	Benign	0.071
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.78	T;T
M_CAP	Benign	0.0097	T
MetaRNN	Benign	0.20	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;.
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-1.2	N;N
REVEL	Benign	0.038
Sift	Benign	0.047	D;D
Sift4G	Uncertain	0.059	T;D
Polyphen		0.095	B;B
Vest4		0.25
MutPred		0.40		.;Gain of catalytic residue at L1246 (P = 0);
MVP		0.15
MPC		0.60
ClinPred		0.77	D
GERP RS		4.3
Varity_R		0.15
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

LitVar

Other links and lift over

dbSNP: rs1941008254; hg19: chr12-31542262;