9-123762933-A-G

Variant names:

• chr9-123762933-A-G
• rs2479106
• NM_001352964.2:c.183-5111T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001352964.2(DENND1A):​c.183-5111T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.426 in 151,984 control chromosomes in the GnomAD database, including 17,040 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.43 (17040 hom., cov: 32)
• Consequence: DENND1A NM_001352964.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.388
• Publications: 77 publications found

Genes affected

DENND1A (HGNC:29324): (DENN domain containing 1A) Clathrin (see MIM 118955)-mediated endocytosis is a major mechanism for internalization of proteins and lipids. Members of the connecdenn family, such as DENND1A, function as guanine nucleotide exchange factors (GEFs) for the early endosomal small GTPase RAB35 (MIM 604199) and bind to clathrin and clathrin adaptor protein-2 (AP2; see MIM 601024). Thus, connecdenns link RAB35 activation with the clathrin machinery (Marat and McPherson, 2010 [PubMed 20154091]).[supplied by OMIM, Nov 2010]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.74 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001352964.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DENND1A	NM_001352964.2	MANE Select	c.183-5111T>C		intron	N/A	NP_001339893.1
	DENND1A	NM_001393654.1		c.183-5111T>C		intron	N/A	NP_001380583.1
	DENND1A	NM_001352965.2		c.87-5111T>C		intron	N/A	NP_001339894.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DENND1A	ENST00000394215.7	TSL:5 MANE Select	c.183-5111T>C		intron	N/A	ENSP00000377763.4
	DENND1A	ENST00000373620.7	TSL:1	c.183-5111T>C		intron	N/A	ENSP00000362722.3
	DENND1A	ENST00000373618.1	TSL:1	c.87-5111T>C		intron	N/A	ENSP00000362720.1

Frequencies

GnomAD3 genomes AF: 0.426 AC: 64669 AN: 151866 Hom.: 16979 Cov.: 32

Gnomad AFR AF: 0.746

Gnomad AMI AF: 0.203

Gnomad AMR AF: 0.305

Gnomad ASJ AF: 0.311

Gnomad EAS AF: 0.184

Gnomad SAS AF: 0.319

Gnomad FIN AF: 0.401

Gnomad MID AF: 0.315

Gnomad NFE AF: 0.299

Gnomad OTH AF: 0.358

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.426 AC: 64805 AN: 151984 Hom.: 17040 Cov.: 32 AF XY: 0.428 AC XY: 31787 AN XY: 74314

African (AFR) AF: 0.747 AC: 30945 AN: 41452

American (AMR) AF: 0.306 AC: 4665 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.311 AC: 1078 AN: 3464

East Asian (EAS) AF: 0.185 AC: 955 AN: 5174

South Asian (SAS) AF: 0.318 AC: 1531 AN: 4810

European-Finnish (FIN) AF: 0.401 AC: 4241 AN: 10568

Middle Eastern (MID) AF: 0.322 AC: 94 AN: 292

European-Non Finnish (NFE) AF: 0.299 AC: 20343 AN: 67948

Other (OTH) AF: 0.365 AC: 769 AN: 2108

Alfa AF: 0.331 Hom.: 44674

Bravo AF: 0.431

Asia WGS AF: 0.296 AC: 1028 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	6.0
DANN	Benign	0.75
PhyloP100		0.39
Mutation Taster		=100/0	polymorphism (auto)

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: rs2479106; hg19: chr9-126525212;