12-31495892-C-T

Variant names:

• chr12-31495892-C-T
• rs4930979
• NM_144973.4:c.155G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_144973.4(DENND5B):​c.155G>A​(p.Arg52Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.402 in 1,608,182 control chromosomes in the GnomAD database, including 136,593 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 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: 𝑓 0.35 (10786 hom., cov: 32)
  • Exomes 𝑓: 0.41 (125807 hom.)
• Consequence: DENND5B NM_144973.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.74
• Publications: 35 publications found

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]

DENND5B Gene-Disease associations (from GenCC):

• neurodevelopmental disorder

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• hypoplastic left heart syndrome

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=8.6658314E-5).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.554 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DENND5B	NM_144973.4	c.155G>A	p.Arg52Lys	missense_variant	Exon 2 of 21	ENST00000389082.10	NP_659410.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DENND5B	ENST00000389082.10	c.155G>A	p.Arg52Lys	missense_variant	Exon 2 of 21	5	NM_144973.4	ENSP00000373734.5

Frequencies

GnomAD3 genomes AF: 0.346 AC: 52520 AN: 151930 Hom.: 10779 Cov.: 32

Gnomad AFR AF: 0.124

Gnomad AMI AF: 0.462

Gnomad AMR AF: 0.539

Gnomad ASJ AF: 0.422

Gnomad EAS AF: 0.572

Gnomad SAS AF: 0.453

Gnomad FIN AF: 0.403

Gnomad MID AF: 0.484

Gnomad NFE AF: 0.396

Gnomad OTH AF: 0.388

GnomAD2 exomes AF: 0.441 AC: 107773 AN: 244636 AF XY: 0.437

Gnomad AFR exome AF: 0.116

Gnomad AMR exome AF: 0.667

Gnomad ASJ exome AF: 0.427

Gnomad EAS exome AF: 0.572

Gnomad FIN exome AF: 0.404

Gnomad NFE exome AF: 0.400

Gnomad OTH exome AF: 0.446

GnomAD4 exome AF: 0.408 AC: 594021 AN: 1456134 Hom.: 125807 Cov.: 35 AF XY: 0.409 AC XY: 296192 AN XY: 724056

African (AFR) AF: 0.113 AC: 3770 AN: 33442

American (AMR) AF: 0.650 AC: 28698 AN: 44182

Ashkenazi Jewish (ASJ) AF: 0.422 AC: 10983 AN: 25998

East Asian (EAS) AF: 0.595 AC: 23539 AN: 39576

South Asian (SAS) AF: 0.451 AC: 38510 AN: 85316

European-Finnish (FIN) AF: 0.412 AC: 21926 AN: 53176

Middle Eastern (MID) AF: 0.454 AC: 2606 AN: 5744

European-Non Finnish (NFE) AF: 0.396 AC: 439495 AN: 1108554

Other (OTH) AF: 0.407 AC: 24494 AN: 60146

GnomAD4 genome AF: 0.345 AC: 52521 AN: 152048 Hom.: 10786 Cov.: 32 AF XY: 0.352 AC XY: 26195 AN XY: 74330

African (AFR) AF: 0.124 AC: 5135 AN: 41502

American (AMR) AF: 0.540 AC: 8249 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.422 AC: 1463 AN: 3468

East Asian (EAS) AF: 0.571 AC: 2952 AN: 5166

South Asian (SAS) AF: 0.453 AC: 2185 AN: 4824

European-Finnish (FIN) AF: 0.403 AC: 4260 AN: 10562

Middle Eastern (MID) AF: 0.476 AC: 140 AN: 294

European-Non Finnish (NFE) AF: 0.396 AC: 26903 AN: 67948

Other (OTH) AF: 0.386 AC: 814 AN: 2110

Alfa AF: 0.386 Hom.: 46061

Bravo AF: 0.348

TwinsUK AF: 0.401 AC: 1488

ALSPAC AF: 0.401 AC: 1544

ESP6500AA AF: 0.126 AC: 458

ESP6500EA AF: 0.402 AC: 3279

ExAC AF: 0.429 AC: 51863

Asia WGS AF: 0.461 AC: 1602 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	18
DANN	Benign	0.97
DEOGEN2	Benign	0.0032	T;T;.;.
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.12
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.81	T;T;T;T
MetaRNN	Benign	0.000087	T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.35	N;.;.;.
PhyloP100		1.7
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-0.15	N;N;N;N
REVEL	Benign	0.048
Sift	Benign	0.27	T;T;T;T
Sift4G	Benign	0.60	T;T;T;T
Polyphen		0.0020	B;B;B;.
Vest4		0.065
MPC		0.54
ClinPred		0.010	T
GERP RS		3.7
PromoterAI		-0.0078	Neutral
Varity_R		0.086
gMVP		0.16
Mutation Taster		=97/3	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4930979; hg19: chr12-31648826; COSMIC: COSV60899945;