8-141144160-T-A

Variant names:

• chr8-141144160-T-A
• rs116789554
• NM_001352890.3:c.636T>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Moderate BP6_Moderate BP7 BS1 BS2

The NM_001352890.3(DENND3):​c.636T>A​(p.Leu212Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0015 in 1,611,200 control chromosomes in the GnomAD database, including 38 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0076 (18 hom., cov: 32)
  • Exomes 𝑓: 0.00085 (20 hom.)
• Consequence: DENND3 NM_001352890.3 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.842
• Publications: 1 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.02).
• BP6: Variant 8-141144160-T-A is Benign according to our data. Variant chr8-141144160-T-A is described in ClinVar as Benign. ClinVar VariationId is 715620.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.842 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00765 (1165/152346) while in subpopulation AFR AF = 0.0267 (1111/41582). AF 95% confidence interval is 0.0254. There are 18 homozygotes in GnomAd4. There are 532 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 18 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.636T>A	p.Leu212Leu	synonymous	Exon 5 of 23	NP_001339819.2	E9PF32
	DENND3	NM_001362798.2		c.636T>A	p.Leu212Leu	synonymous	Exon 5 of 22	NP_001349727.1
	DENND3	NM_014957.5		c.435T>A	p.Leu145Leu	synonymous	Exon 5 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.636T>A	p.Leu212Leu	synonymous	Exon 5 of 23	ENSP00000428714.1	E9PF32
	DENND3	ENST00000424248.2	TSL:1	c.396T>A	p.Leu132Leu	synonymous	Exon 4 of 21	ENSP00000410594.1	A2RUS2-2
	DENND3	ENST00000885117.1		c.636T>A	p.Leu212Leu	synonymous	Exon 5 of 23	ENSP00000555176.1

Frequencies

GnomAD3 genomes AF: 0.00766 AC: 1166 AN: 152228 Hom.: 18 Cov.: 32

Gnomad AFR AF: 0.0268

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00242

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: 0.000132

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00212 AC: 525 AN: 248206 AF XY: 0.00161

Gnomad AFR exome AF: 0.0281

Gnomad AMR exome AF: 0.00161

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000115

Gnomad OTH exome AF: 0.000658

GnomAD4 exome AF: 0.000853 AC: 1244 AN: 1458854 Hom.: 20 Cov.: 30 AF XY: 0.000726 AC XY: 527 AN XY: 725672

African (AFR) AF: 0.0281 AC: 930 AN: 33152

American (AMR) AF: 0.00184 AC: 81 AN: 43910

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26058

East Asian (EAS) AF: 0.00 AC: 0 AN: 39618

South Asian (SAS) AF: 0.0000938 AC: 8 AN: 85314

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00122 AC: 7 AN: 5758

European-Non Finnish (NFE) AF: 0.0000909 AC: 101 AN: 1111354

Other (OTH) AF: 0.00194 AC: 117 AN: 60288

GnomAD4 genome AF: 0.00765 AC: 1165 AN: 152346 Hom.: 18 Cov.: 32 AF XY: 0.00714 AC XY: 532 AN XY: 74500

African (AFR) AF: 0.0267 AC: 1111 AN: 41582

American (AMR) AF: 0.00242 AC: 37 AN: 15306

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68022

Other (OTH) AF: 0.00378 AC: 8 AN: 2116

Alfa AF: 0.00241 Hom.: 4

Bravo AF: 0.00867

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

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
BayesDel_noAF	Benign	-0.68
CADD	Benign	0.56
DANN	Benign	0.71
PhyloP100		-0.84
Mutation Taster		=100/0	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: rs116789554; hg19: chr8-142154259;