rs12348586

Positions:

• chr9-123399109-A-C
• chr9-123399109-A-G

Variant summary

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

The NM_001352964.2(DENND1A):​c.1631+4293T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.134 in 151,938 control chromosomes in the GnomAD database, including 1,415 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 0.13 (1415 hom., cov: 32)
• Consequence: DENND1A NM_001352964.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.510

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=-0.87).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.176 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DENND1A	NM_001352964.2	c.1631+4293T>G		intron_variant		ENST00000394215.7	NP_001339893.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DENND1A	ENST00000394215.7	c.1631+4293T>G		intron_variant		5	NM_001352964.2	ENSP00000377763	A2
DENND1A	ENST00000473039.5	n.1440+4293T>G		intron_variant, non_coding_transcript_variant		1
DENND1A	ENST00000373624.6	c.1577+4293T>G		intron_variant		5		ENSP00000362727	P2

Frequencies

GnomAD3 genomes AF: 0.134 AC: 20378 AN: 151820 Hom.: 1405 Cov.: 32

Gnomad AFR AF: 0.130

Gnomad AMI AF: 0.145

Gnomad AMR AF: 0.180

Gnomad ASJ AF: 0.0577

Gnomad EAS AF: 0.0912

Gnomad SAS AF: 0.133

Gnomad FIN AF: 0.192

Gnomad MID AF: 0.0732

Gnomad NFE AF: 0.125

Gnomad OTH AF: 0.143

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

GnomAD4 genome AF: 0.134 AC: 20409 AN: 151938 Hom.: 1415 Cov.: 32 AF XY: 0.139 AC XY: 10286 AN XY: 74230

Gnomad4 AFR AF: 0.130

Gnomad4 AMR AF: 0.182

Gnomad4 ASJ AF: 0.0577

Gnomad4 EAS AF: 0.0910

Gnomad4 SAS AF: 0.133

Gnomad4 FIN AF: 0.192

Gnomad4 NFE AF: 0.125

Gnomad4 OTH AF: 0.141

Alfa AF: 0.127 Hom.: 602

Bravo AF: 0.134

Asia WGS AF: 0.0950 AC: 331 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	4.4
DANN	Benign	0.77

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: rs12348586; hg19: chr9-126161388;