NM_014856.3:c.3419A>T

Variant names:

• chr1-153933231-T-A
• rs200470601
• NM_014856.3:c.3419A>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_014856.3(DENND4B):​c.3419A>T​(p.Asp1140Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000586 in 1,612,982 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00059 (0 hom.)
• Consequence: DENND4B NM_014856.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.77
• Publications: 3 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.066688985).

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.3419A>T	p.Asp1140Val	missense	Exon 21 of 28	NP_055671.2
	DENND4B	NM_001367466.1		c.3452A>T	p.Asp1151Val	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.3419A>T	p.Asp1140Val	missense	Exon 21 of 28	ENSP00000354597.4	O75064
	DENND4B	ENST00000877431.1		c.3422A>T	p.Asp1141Val	missense	Exon 21 of 28	ENSP00000547490.1
	DENND4B	ENST00000912808.1		c.3422A>T	p.Asp1141Val	missense	Exon 21 of 28	ENSP00000582867.1

Frequencies

GnomAD3 genomes AF: 0.000533 AC: 81 AN: 152064 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000868

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.000404 AC: 100 AN: 247508 AF XY: 0.000447

Gnomad AFR exome AF: 0.000131

Gnomad AMR exome AF: 0.000642

Gnomad ASJ exome AF: 0.000499

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000633

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000592 AC: 865 AN: 1460918 Hom.: 0 Cov.: 33 AF XY: 0.000596 AC XY: 433 AN XY: 726636

African (AFR) AF: 0.0000598 AC: 2 AN: 33472

American (AMR) AF: 0.000650 AC: 29 AN: 44584

Ashkenazi Jewish (ASJ) AF: 0.000268 AC: 7 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.00 AC: 0 AN: 86038

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53352

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

European-Non Finnish (NFE) AF: 0.000713 AC: 792 AN: 1111538

Other (OTH) AF: 0.000580 AC: 35 AN: 60366

GnomAD4 genome AF: 0.000533 AC: 81 AN: 152064 Hom.: 0 Cov.: 32 AF XY: 0.000458 AC XY: 34 AN XY: 74280

African (AFR) AF: 0.000290 AC: 12 AN: 41408

American (AMR) AF: 0.000458 AC: 7 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000868 AC: 59 AN: 68006

Other (OTH) AF: 0.00143 AC: 3 AN: 2092

Alfa AF: 0.000563 Hom.: 0

Bravo AF: 0.000491

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000834 AC: 7

ExAC AF: 0.000389 AC: 47

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	0.14
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.39
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.027	T
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.0089	T
MetaRNN	Benign	0.067	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L
PhyloP100		2.8
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.12
Sift	Uncertain	0.0030	D
Sift4G	Benign	0.28	T
Polyphen		0.76	P
Vest4		0.26
MVP		0.082
MPC		0.30
ClinPred		0.071	T
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.11
gMVP		0.54
Mutation Taster		=80/20	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs200470601; hg19: chr1-153905707;