19-6475602-T-C

Variant names:

• chr19-6475602-T-C
• rs3745571
• NM_024898.4:c.826-17A>G

Variant summary

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

The NM_024898.4(DENND1C):​c.826-17A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.621 in 1,613,568 control chromosomes in the GnomAD database, including 318,251 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 0.56 (24227 hom., cov: 33)
  • Exomes 𝑓: 0.63 (294024 hom.)
• Consequence: DENND1C NM_024898.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.57

Genes affected

DENND1C (HGNC:26225): (DENN domain containing 1C) The protein encoded by this gene functions as a guanine nucleotide exchange factor for the early endosomal small GTPase RAB35, which regulates endosomal membrane trafficking and is involved in actin polymerization. The encoded protein activates RAB35 by promoting the exchange of RAB35-bound GDP for GTP. This gene may play a role in linking RAB35 activation with the clathrin machinery. [provided by RefSeq, May 2017]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.642 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DENND1C	NM_024898.4	c.826-17A>G		intron_variant	Intron 12 of 22	ENST00000381480.7	NP_079174.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DENND1C	ENST00000381480.7	c.826-17A>G		intron_variant	Intron 12 of 22	1	NM_024898.4	ENSP00000370889.1

Frequencies

GnomAD3 genomes AF: 0.555 AC: 84332 AN: 151908 Hom.: 24217 Cov.: 33

Gnomad AFR AF: 0.445

Gnomad AMI AF: 0.800

Gnomad AMR AF: 0.525

Gnomad ASJ AF: 0.613

Gnomad EAS AF: 0.325

Gnomad SAS AF: 0.520

Gnomad FIN AF: 0.533

Gnomad MID AF: 0.456

Gnomad NFE AF: 0.647

Gnomad OTH AF: 0.530

GnomAD3 exomes AF: 0.561 AC: 139607 AN: 248876 Hom.: 40541 AF XY: 0.566 AC XY: 76466 AN XY: 135038

Gnomad AFR exome AF: 0.435

Gnomad AMR exome AF: 0.480

Gnomad ASJ exome AF: 0.621

Gnomad EAS exome AF: 0.337

Gnomad SAS exome AF: 0.537

Gnomad FIN exome AF: 0.540

Gnomad NFE exome AF: 0.643

Gnomad OTH exome AF: 0.579

GnomAD4 exome AF: 0.628 AC: 918084 AN: 1461542 Hom.: 294024 Cov.: 62 AF XY: 0.625 AC XY: 454199 AN XY: 727054

Gnomad4 AFR exome AF: 0.434

Gnomad4 AMR exome AF: 0.489

Gnomad4 ASJ exome AF: 0.615

Gnomad4 EAS exome AF: 0.309

Gnomad4 SAS exome AF: 0.536

Gnomad4 FIN exome AF: 0.549

Gnomad4 NFE exome AF: 0.664

Gnomad4 OTH exome AF: 0.599

GnomAD4 genome AF: 0.555 AC: 84385 AN: 152026 Hom.: 24227 Cov.: 33 AF XY: 0.548 AC XY: 40735 AN XY: 74324

Gnomad4 AFR AF: 0.445

Gnomad4 AMR AF: 0.525

Gnomad4 ASJ AF: 0.613

Gnomad4 EAS AF: 0.325

Gnomad4 SAS AF: 0.521

Gnomad4 FIN AF: 0.533

Gnomad4 NFE AF: 0.647

Gnomad4 OTH AF: 0.532

Alfa AF: 0.625 Hom.: 57331

Bravo AF: 0.553

Asia WGS AF: 0.423 AC: 1470 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.087
DANN	Benign	0.35

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs3745571; hg19: chr19-6475613; COSMIC: COSV67372099; COSMIC: COSV67372099;