8-141136755-G-A

Variant names:

• chr8-141136755-G-A
• rs144082723
• NM_001352890.3:c.349G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001352890.3(DENND3):​c.349G>A​(p.Val117Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000464 in 1,594,242 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0025 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00025 (3 hom.)
• Consequence: DENND3 NM_001352890.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.39
• Publications: 2 publications found

Genes affected

DENND3 (HGNC:29134): (DENN domain containing 3) Enables guanyl-nucleotide exchange factor activity. Predicted to be involved in cellular protein catabolic process; endosome to lysosome transport; and regulation of Rab protein signal transduction. Predicted to be located in cytosol. Predicted to be active in cytoplasmic vesicle. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008565903).
• BP6: Variant 8-141136755-G-A is Benign according to our data. Variant chr8-141136755-G-A is described in ClinVar as Benign. ClinVar VariationId is 726082.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001352890.3. 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
	DENND3	NM_001352890.3	MANE Select	c.349G>A	p.Val117Met	missense	Exon 2 of 23	NP_001339819.2	E9PF32
	DENND3	NM_001362798.2		c.349G>A	p.Val117Met	missense	Exon 2 of 22	NP_001349727.1
	DENND3	NM_014957.5		c.148G>A	p.Val50Met	missense	Exon 2 of 23	NP_055772.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DENND3	ENST00000519811.6	TSL:5 MANE Select	c.349G>A	p.Val117Met	missense	Exon 2 of 23	ENSP00000428714.1	E9PF32
	DENND3	ENST00000424248.2	TSL:1	c.109G>A	p.Val37Met	missense	Exon 1 of 21	ENSP00000410594.1	A2RUS2-2
	DENND3	ENST00000885117.1		c.349G>A	p.Val117Met	missense	Exon 2 of 23	ENSP00000555176.1

Frequencies

GnomAD3 genomes AF: 0.00250 AC: 381 AN: 152164 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00888

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.000500 AC: 104 AN: 207952 AF XY: 0.000417

Gnomad AFR exome AF: 0.00825

Gnomad AMR exome AF: 0.000101

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000110

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000248 AC: 358 AN: 1441960 Hom.: 3 Cov.: 34 AF XY: 0.000201 AC XY: 144 AN XY: 715658

African (AFR) AF: 0.00915 AC: 303 AN: 33106

American (AMR) AF: 0.000170 AC: 7 AN: 41228

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25622

East Asian (EAS) AF: 0.0000257 AC: 1 AN: 38902

South Asian (SAS) AF: 0.0000120 AC: 1 AN: 83308

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51446

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5650

European-Non Finnish (NFE) AF: 0.0000127 AC: 14 AN: 1103078

Other (OTH) AF: 0.000537 AC: 32 AN: 59620

GnomAD4 genome AF: 0.00251 AC: 382 AN: 152282 Hom.: 1 Cov.: 33 AF XY: 0.00228 AC XY: 170 AN XY: 74456

African (AFR) AF: 0.00888 AC: 369 AN: 41560

American (AMR) AF: 0.000392 AC: 6 AN: 15302

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68026

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.000955 Hom.: 1

Bravo AF: 0.00273

ESP6500AA AF: 0.00797 AC: 35

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000680 AC: 82

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.37
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.023	T
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.78	T
MetaRNN	Benign	0.0086	T
MetaSVM	Benign	-0.79	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		2.4
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.11
Sift	Benign	0.14	T
Sift4G	Benign	0.12	T
Polyphen		0.96	D
Vest4		0.34
MVP		0.67
MPC		1.3
ClinPred		0.036	T
GERP RS		5.6
PromoterAI		0.045	Neutral
Varity_R		0.069
gMVP		0.37
Mutation Taster		=97/3	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: rs144082723; hg19: chr8-142146854;