1-153933524-G-T

Position:

• chr1-153933524-G-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2 BP4_Moderate BS2

The NM_014856.3(DENND4B):​c.3289C>A​(p.Leu1097Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000015 in 1,399,652 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: DENND4B NM_014856.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.81

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]

(HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), DENND4B. . Gene score misZ 3.2312 (greater than the threshold 3.09). Trascript score misZ 4.0136 (greater than threshold 3.09). GenCC has associacion of gene with isolated cleft palate.
• BP4: Computational evidence support a benign effect (MetaRNN=0.112840354).
• BS2: High AC in GnomAdExome4 at 21 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DENND4B	NM_014856.3	c.3289C>A	p.Leu1097Ile	missense_variant	20/28	ENST00000361217.9
LOC101928059	XR_922160.3	n.925-1212G>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DENND4B	ENST00000361217.9	c.3289C>A	p.Leu1097Ile	missense_variant	20/28	1	NM_014856.3	P1
	ENST00000641448.2	n.816-1212G>T		intron_variant, non_coding_transcript_variant
DENND4B	ENST00000368646.6	c.3322C>A	p.Leu1108Ile	missense_variant	20/22	5
	ENST00000641267.1	n.763-1225G>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000150 AC: 21 AN: 1399652 Hom.: 0 Cov.: 33 AF XY: 0.0000102 AC XY: 7 AN XY: 689520

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000194

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 14, 2022

The c.3289C>A (p.L1097I) alteration is located in exon 20 (coding exon 19) of the DENND4B gene. This alteration results from a C to A substitution at nucleotide position 3289, causing the leucine (L) at amino acid position 1097 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.014	T;.
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.10
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.60	T;T
M_CAP	Benign	0.0081	T
MetaRNN	Benign	0.11	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.4	L;.
MutationTaster	Benign	0.89	N
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.85	N;N
REVEL	Benign	0.043
Sift	Uncertain	0.022	D;T
Sift4G	Benign	0.28	T;.
Polyphen		0.0060	B;.
Vest4		0.24
MutPred		0.32		Loss of methylation at R1101 (P = 0.2649);.;
MVP		0.043
MPC		0.44
ClinPred		0.53	D
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.13
gMVP		0.41

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs752750941; hg19: chr1-153906000;