chr12-31495892-C-A

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_144973.4(DENND5B):​c.155G>T​(p.Arg52Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_144973.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DENND5B	NM_144973.4	MANE Select	c.155G>T	p.Arg52Ile	missense	Exon 2 of 21	NP_659410.3
	DENND5B	NM_001308339.2		c.260G>T	p.Arg87Ile	missense	Exon 4 of 23	NP_001295268.1
	DENND5B	NM_001366890.1		c.221G>T	p.Arg74Ile	missense	Exon 3 of 9	NP_001353819.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DENND5B	ENST00000389082.10	TSL:5 MANE Select	c.155G>T	p.Arg52Ile	missense	Exon 2 of 21	ENSP00000373734.5
	DENND5B	ENST00000354285.8	TSL:1	c.221G>T	p.Arg74Ile	missense	Exon 3 of 9	ENSP00000346238.4
	DENND5B	ENST00000546299.1	TSL:1	c.11G>T	p.Arg4Ile	missense	Exon 1 of 4	ENSP00000442938.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Benign	-0.064	T
BayesDel_noAF	Benign	-0.33
CADD	Uncertain	26
DANN	Uncertain	0.98
DEOGEN2	Benign	0.17	T
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.025	T
MetaRNN	Uncertain	0.61	D
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	1.9	L
PhyloP100		1.7
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-3.3	D
REVEL	Uncertain	0.31
Sift	Uncertain	0.015	D
Sift4G	Uncertain	0.059	T
Polyphen		0.90	P
Vest4		0.60
MutPred		0.53		Loss of disorder (P = 0.0187)
MVP		0.23
MPC		1.4
ClinPred		0.93	D
GERP RS		3.7
PromoterAI		-0.025	Neutral
Varity_R		0.18
gMVP		0.33
Mutation Taster		=81/19	polymorphism

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;