rs77142252

Variant names:

• chr8-141151720-G-A
• rs77142252
• NM_001352890.3:c.957G>A

Your query was ambiguous. Multiple possible variants found:

• chr8-141151720-G-A
• chr8-141151720-G-T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4 BP6_Very_Strong BP7 BS1 BS2

The NM_001352890.3(DENND3):​c.957G>A​(p.Pro319Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00114 in 1,614,160 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0058 (11 hom., cov: 32)
  • Exomes 𝑓: 0.00066 (8 hom.)
• Consequence: DENND3 NM_001352890.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.24
• Publications: 3 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.251).
• BP6: Variant 8-141151720-G-A is Benign according to our data. Variant chr8-141151720-G-A is described in ClinVar as Benign. ClinVar VariationId is 711020.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.24 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00581 (884/152266) while in subpopulation AFR AF = 0.0194 (805/41556). AF 95% confidence interval is 0.0183. There are 11 homozygotes in GnomAd4. There are 410 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 11 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.957G>A	p.Pro319Pro	synonymous	Exon 7 of 23	NP_001339819.2	E9PF32
	DENND3	NM_001362798.2		c.957G>A	p.Pro319Pro	synonymous	Exon 7 of 22	NP_001349727.1
	DENND3	NM_014957.5		c.756G>A	p.Pro252Pro	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.957G>A	p.Pro319Pro	synonymous	Exon 7 of 23	ENSP00000428714.1	E9PF32
	DENND3	ENST00000424248.2	TSL:1	c.717G>A	p.Pro239Pro	synonymous	Exon 6 of 21	ENSP00000410594.1	A2RUS2-2
	DENND3	ENST00000885117.1		c.957G>A	p.Pro319Pro	synonymous	Exon 7 of 23	ENSP00000555176.1

Frequencies

GnomAD3 genomes AF: 0.00575 AC: 875 AN: 152148 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.0192

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00419

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: 0.0000882

Gnomad OTH AF: 0.00430

GnomAD2 exomes AF: 0.00153 AC: 384 AN: 251492 AF XY: 0.00118

Gnomad AFR exome AF: 0.0191

Gnomad AMR exome AF: 0.00147

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000114

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.000655 AC: 958 AN: 1461894 Hom.: 8 Cov.: 33 AF XY: 0.000579 AC XY: 421 AN XY: 727248

African (AFR) AF: 0.0200 AC: 670 AN: 33480

American (AMR) AF: 0.00159 AC: 71 AN: 44724

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

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

South Asian (SAS) AF: 0.000104 AC: 9 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00191 AC: 11 AN: 5768

European-Non Finnish (NFE) AF: 0.000104 AC: 116 AN: 1112012

Other (OTH) AF: 0.00134 AC: 81 AN: 60396

GnomAD4 genome AF: 0.00581 AC: 884 AN: 152266 Hom.: 11 Cov.: 32 AF XY: 0.00551 AC XY: 410 AN XY: 74442

African (AFR) AF: 0.0194 AC: 805 AN: 41556

American (AMR) AF: 0.00418 AC: 64 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10594

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

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68028

Other (OTH) AF: 0.00426 AC: 9 AN: 2114

Alfa AF: 0.000447 Hom.: 0

Bravo AF: 0.00635

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	4.3
DANN	Benign	0.72
PhyloP100		-3.2
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs77142252; hg19: chr8-142161819;