rs1539414

Positions:

• chr1-197774376-G-A

Variant summary

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

The NM_001195215.2(DENND1B):​c.17+763C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.234 in 152,050 control chromosomes in the GnomAD database, including 4,483 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 0.23 (4483 hom., cov: 33)
  • Exomes 𝑓: 0.50 (0 hom.)
• Consequence: DENND1B NM_001195215.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0780

Genes affected

DENND1B (HGNC:28404): (DENN domain containing 1B) Clathrin (see MIM 118955)-mediated endocytosis is a major mechanism for internalization of proteins and lipids. Members of the connecdenn family, such as DENND1B, 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 = 0.301 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DENND1B	NM_001195215.2	c.17+763C>T		intron_variant		ENST00000620048.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DENND1B	ENST00000620048.6	c.17+763C>T		intron_variant		5	NM_001195215.2	P2

Frequencies

GnomAD3 genomes AF: 0.234 AC: 35556 AN: 151930 Hom.: 4476 Cov.: 33

Gnomad AFR AF: 0.305

Gnomad AMI AF: 0.122

Gnomad AMR AF: 0.207

Gnomad ASJ AF: 0.192

Gnomad EAS AF: 0.207

Gnomad SAS AF: 0.246

Gnomad FIN AF: 0.136

Gnomad MID AF: 0.335

Gnomad NFE AF: 0.216

Gnomad OTH AF: 0.238

GnomAD4 exome AF: 0.500 AC: 1 AN: 2 Hom.: 0 AF XY: 0.500 AC XY: 1 AN XY: 2

Gnomad4 FIN exome AF: 0.500

GnomAD4 genome AF: 0.234 AC: 35584 AN: 152048 Hom.: 4483 Cov.: 33 AF XY: 0.229 AC XY: 17008 AN XY: 74320

Gnomad4 AFR AF: 0.305

Gnomad4 AMR AF: 0.206

Gnomad4 ASJ AF: 0.192

Gnomad4 EAS AF: 0.206

Gnomad4 SAS AF: 0.246

Gnomad4 FIN AF: 0.136

Gnomad4 NFE AF: 0.216

Gnomad4 OTH AF: 0.240

Alfa AF: 0.218 Hom.: 1965

Bravo AF: 0.240

Asia WGS AF: 0.278 AC: 963 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.0
DANN	Benign	0.26

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: rs1539414; hg19: chr1-197743506; COSMIC: COSV52462535;