NM_014856.3:c.4303T>C

Variant names:

• chr1-153930581-A-G
• rs1430881375
• NM_014856.3:c.4303T>C

Variant summary

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

The NM_014856.3(DENND4B):​c.4303T>C​(p.Phe1435Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,708 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: DENND4B NM_014856.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.47
• Publications: 1 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 2 ACMG points.

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

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.4303T>C	p.Phe1435Leu	missense	Exon 27 of 28	NP_055671.2
	DENND4B	NM_001367466.1		c.4336T>C	p.Phe1446Leu	missense	Exon 27 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.4303T>C	p.Phe1435Leu	missense	Exon 27 of 28	ENSP00000354597.4	O75064
	DENND4B	ENST00000877431.1		c.4306T>C	p.Phe1436Leu	missense	Exon 27 of 28	ENSP00000547490.1
	DENND4B	ENST00000912808.1		c.4306T>C	p.Phe1436Leu	missense	Exon 27 of 28	ENSP00000582867.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000401 AC: 1 AN: 249216 AF XY: 0.00000740

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461708 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727138

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111868

Other (OTH) AF: 0.00 AC: 0 AN: 60374

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

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	Pathogenic	0.96
BayesDel_addAF	Benign	-0.030	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.36	T
Eigen	Benign	0.053
Eigen_PC	Uncertain	0.22
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.0091	T
MetaRNN	Uncertain	0.48	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L
PhyloP100		6.5
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-4.7	D
REVEL	Benign	0.25
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.085	T
Polyphen		0.048	B
Vest4		0.74
MutPred		0.58		Gain of MoRF binding (P = 0.5067)
MVP		0.29
MPC		1.9
ClinPred		0.98	D
GERP RS		5.1
Varity_R		0.68
gMVP		0.86
Mutation Taster		=57/43	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: rs1430881375; hg19: chr1-153903057;