8-141151813-C-T

Variant names:

• chr8-141151813-C-T
• rs142459324
• NM_001352890.3:c.1050C>T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_001352890.3(DENND3):​c.1050C>T​(p.Leu350Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000517 in 1,614,188 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00072 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00050 (5 hom.)
• Consequence: DENND3 NM_001352890.3 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.70
• Publications: 0 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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 8-141151813-C-T is Benign according to our data. Variant chr8-141151813-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2658870.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-1.7 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 5 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.1050C>T	p.Leu350Leu	synonymous	Exon 7 of 23	NP_001339819.2	E9PF32
	DENND3	NM_001362798.2		c.1050C>T	p.Leu350Leu	synonymous	Exon 7 of 22	NP_001349727.1
	DENND3	NM_014957.5		c.849C>T	p.Leu283Leu	synonymous	Exon 7 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.1050C>T	p.Leu350Leu	synonymous	Exon 7 of 23	ENSP00000428714.1	E9PF32
	DENND3	ENST00000424248.2	TSL:1	c.810C>T	p.Leu270Leu	synonymous	Exon 6 of 21	ENSP00000410594.1	A2RUS2-2
	DENND3	ENST00000885117.1		c.1050C>T	p.Leu350Leu	synonymous	Exon 7 of 23	ENSP00000555176.1

Frequencies

GnomAD3 genomes AF: 0.000723 AC: 110 AN: 152224 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00229

Gnomad ASJ AF: 0.0179

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00103 AC: 258 AN: 251478 AF XY: 0.000898

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000752

Gnomad ASJ exome AF: 0.0187

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000246

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.000495 AC: 724 AN: 1461846 Hom.: 5 Cov.: 34 AF XY: 0.000484 AC XY: 352 AN XY: 727222

African (AFR) AF: 0.0000597 AC: 2 AN: 33478

American (AMR) AF: 0.000783 AC: 35 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0182 AC: 476 AN: 26136

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

South Asian (SAS) AF: 0.000116 AC: 10 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5744

European-Non Finnish (NFE) AF: 0.000101 AC: 112 AN: 1112010

Other (OTH) AF: 0.00147 AC: 89 AN: 60394

GnomAD4 genome AF: 0.000722 AC: 110 AN: 152342 Hom.: 0 Cov.: 33 AF XY: 0.000792 AC XY: 59 AN XY: 74484

African (AFR) AF: 0.00 AC: 0 AN: 41580

American (AMR) AF: 0.00229 AC: 35 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0179 AC: 62 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

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

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68044

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

Alfa AF: 0.00190 Hom.: 0

Bravo AF: 0.000914

EpiCase AF: 0.000164

EpiControl AF: 0.000474

ClinVar

ClinVar submissions as Germline

Significance: Likely 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
BayesDel_noAF	Benign	-0.73
CADD	Benign	1.8
DANN	Benign	0.62
PhyloP100		-1.7

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: rs142459324; hg19: chr8-142161912;