9-123404460-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001352964.2(DENND1A):c.1543-970G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.185 in 152,196 control chromosomes in the GnomAD database, including 3,122 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 0.18 (3122 hom., cov: 32)
• Consequence: DENND1A NM_001352964.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.19

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

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.303 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DENND1A	NM_001352964.2	c.1543-970G>A		intron_variant		ENST00000394215.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DENND1A	ENST00000394215.7	c.1543-970G>A		intron_variant		5	NM_001352964.2	A2

Frequencies

GnomAD3 genomes AF: 0.185 AC: 28067 AN: 152078 Hom.: 3111 Cov.: 32

Gnomad AFR AF: 0.308

Gnomad AMI AF: 0.145

Gnomad AMR AF: 0.194

Gnomad ASJ AF: 0.0631

Gnomad EAS AF: 0.0929

Gnomad SAS AF: 0.133

Gnomad FIN AF: 0.191

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.125

Gnomad OTH AF: 0.177

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

GnomAD4 genome AF: 0.185 AC: 28118 AN: 152196 Hom.: 3122 Cov.: 32 AF XY: 0.187 AC XY: 13928 AN XY: 74418

Gnomad4 AFR AF: 0.308

Gnomad4 AMR AF: 0.195

Gnomad4 ASJ AF: 0.0631

Gnomad4 EAS AF: 0.0925

Gnomad4 SAS AF: 0.133

Gnomad4 FIN AF: 0.191

Gnomad4 NFE AF: 0.125

Gnomad4 OTH AF: 0.175

Alfa AF: 0.125 Hom.: 1763

Bravo AF: 0.192

Asia WGS AF: 0.101 AC: 351 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
Cadd	Benign	0.13
Dann	Benign	0.65

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

Publications

LitVar

Other links and lift over

dbSNP: rs7865976; hg19: chr9-126166739; COSMIC: COSV65337041; COSMIC: COSV65337041;