rs941498029

Variant names:

• chr1-153933255-C-T
• rs941498029
• NM_014856.3:c.3395G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014856.3(DENND4B):​c.3395G>A​(p.Arg1132His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,460,818 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1132L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: DENND4B NM_014856.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.420
• Publications: 0 publications found

Genes affected

DENND4B (HGNC:29044): (DENN domain containing 4B) Enables guanyl-nucleotide exchange factor activity. Involved in regulation of Rab protein signal transduction. Located in Golgi apparatus and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

DENND4B Gene-Disease associations (from GenCC):

• isolated cleft palate

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ENSG00000284738 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06888524).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014856.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DENND4B	NM_014856.3	MANE Select	c.3395G>A	p.Arg1132His	missense	Exon 21 of 28	NP_055671.2
	DENND4B	NM_001367466.1		c.3428G>A	p.Arg1143His	missense	Exon 21 of 28	NP_001354395.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DENND4B	ENST00000361217.9	TSL:1 MANE Select	c.3395G>A	p.Arg1132His	missense	Exon 21 of 28	ENSP00000354597.4	O75064
	DENND4B	ENST00000877431.1		c.3398G>A	p.Arg1133His	missense	Exon 21 of 28	ENSP00000547490.1
	DENND4B	ENST00000912808.1		c.3398G>A	p.Arg1133His	missense	Exon 21 of 28	ENSP00000582867.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000809 AC: 2 AN: 247220 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000560

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000892

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1460818 Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3 AN XY: 726568

African (AFR) AF: 0.0000896 AC: 3 AN: 33468

American (AMR) AF: 0.00 AC: 0 AN: 44570

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26112

East Asian (EAS) AF: 0.00 AC: 0 AN: 39670

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86024

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53340

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111516

Other (OTH) AF: 0.00 AC: 0 AN: 60350

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.024	T
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.17
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.069	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.1	L
PhyloP100		0.42
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.17	N
REVEL	Benign	0.11
Sift	Benign	0.10	T
Sift4G	Benign	0.52	T
Polyphen		0.0020	B
Vest4		0.063
MutPred		0.28		Loss of MoRF binding (P = 0.1076)
MVP		0.068
MPC		0.16
ClinPred		0.26	T
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.037
gMVP		0.60
Mutation Taster		=96/4	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: rs941498029; hg19: chr1-153905731;