19-6475602-T-C

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 20 publications found

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

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024898.4. 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
	DENND1C	NM_024898.4	MANE Select	c.826-17A>G		intron	N/A	NP_079174.2	Q8IV53-1
	DENND1C	NM_001290331.2		c.694-17A>G		intron	N/A	NP_001277260.1	Q8IV53-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DENND1C	ENST00000381480.7	TSL:1 MANE Select	c.826-17A>G		intron	N/A	ENSP00000370889.1	Q8IV53-1
	DENND1C	ENST00000590867.5	TSL:1	n.*41A>G		non_coding_transcript_exon	Exon 11 of 21	ENSP00000465675.1	K7EKL5
	DENND1C	ENST00000590867.5	TSL:1	n.*41A>G		3_prime_UTR	Exon 11 of 21	ENSP00000465675.1	K7EKL5

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

GnomAD2 exomes AF: 0.561 AC: 139607 AN: 248876 AF XY: 0.566

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 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

African (AFR) AF: 0.434 AC: 14542 AN: 33478

American (AMR) AF: 0.489 AC: 21884 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.615 AC: 16082 AN: 26130

East Asian (EAS) AF: 0.309 AC: 12280 AN: 39698

South Asian (SAS) AF: 0.536 AC: 46246 AN: 86256

European-Finnish (FIN) AF: 0.549 AC: 29290 AN: 53344

Middle Eastern (MID) AF: 0.531 AC: 3061 AN: 5766

European-Non Finnish (NFE) AF: 0.664 AC: 738527 AN: 1111790

Other (OTH) AF: 0.599 AC: 36172 AN: 60370

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

African (AFR) AF: 0.445 AC: 18431 AN: 41426

American (AMR) AF: 0.525 AC: 8025 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.613 AC: 2124 AN: 3466

East Asian (EAS) AF: 0.325 AC: 1682 AN: 5170

South Asian (SAS) AF: 0.521 AC: 2514 AN: 4828

European-Finnish (FIN) AF: 0.533 AC: 5638 AN: 10574

Middle Eastern (MID) AF: 0.452 AC: 133 AN: 294

European-Non Finnish (NFE) AF: 0.647 AC: 43991 AN: 67956

Other (OTH) AF: 0.532 AC: 1122 AN: 2110

Alfa AF: 0.608 Hom.: 91595

Bravo AF: 0.553

Asia WGS AF: 0.423 AC: 1470 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.087
DANN	Benign	0.35
PhyloP100		-1.6
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3745571; hg19: chr19-6475613; COSMIC: COSV67372099; COSMIC: COSV67372099;