rs10494757

Variant names:

• chr1-197538281-C-T
• rs10494757
• NM_001195215.2:c.1515+1683G>A

Variant summary

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

The NM_001195215.2(DENND1B):​c.1515+1683G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0464 in 151,900 control chromosomes in the GnomAD database, including 240 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 0.046 (240 hom., cov: 32)
• Consequence: DENND1B NM_001195215.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.326
• Publications: 5 publications found

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

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0685 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001195215.2. 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
	DENND1B	NM_001195215.2	MANE Select	c.1515+1683G>A		intron	N/A	NP_001182144.1	Q6P3S1-1
	DENND1B	NR_125340.2		n.1587+1683G>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DENND1B	ENST00000620048.6	TSL:5 MANE Select	c.1515+1683G>A		intron	N/A	ENSP00000479816.1	Q6P3S1-1
	DENND1B	ENST00000887109.1		c.1461+1683G>A		intron	N/A	ENSP00000557168.1
	DENND1B	ENST00000887105.1		c.1455+1683G>A		intron	N/A	ENSP00000557164.1

Frequencies

GnomAD3 genomes AF: 0.0464 AC: 7050 AN: 151782 Hom.: 240 Cov.: 32

Gnomad AFR AF: 0.0109

Gnomad AMI AF: 0.0406

Gnomad AMR AF: 0.0458

Gnomad ASJ AF: 0.0695

Gnomad EAS AF: 0.000580

Gnomad SAS AF: 0.0175

Gnomad FIN AF: 0.0628

Gnomad MID AF: 0.0318

Gnomad NFE AF: 0.0701

Gnomad OTH AF: 0.0484

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

GnomAD4 genome AF: 0.0464 AC: 7052 AN: 151900 Hom.: 240 Cov.: 32 AF XY: 0.0454 AC XY: 3370 AN XY: 74222

African (AFR) AF: 0.0109 AC: 452 AN: 41452

American (AMR) AF: 0.0458 AC: 699 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.0695 AC: 241 AN: 3468

East Asian (EAS) AF: 0.000581 AC: 3 AN: 5164

South Asian (SAS) AF: 0.0177 AC: 85 AN: 4808

European-Finnish (FIN) AF: 0.0628 AC: 659 AN: 10496

Middle Eastern (MID) AF: 0.0377 AC: 11 AN: 292

European-Non Finnish (NFE) AF: 0.0701 AC: 4763 AN: 67926

Other (OTH) AF: 0.0483 AC: 102 AN: 2110

Alfa AF: 0.0655 Hom.: 329

Bravo AF: 0.0431

Asia WGS AF: 0.0120 AC: 40 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.12
DANN	Benign	0.68
PhyloP100		-0.33

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs10494757;

hg19: chr1-197507411;