rs10519304

Variant names:

• chr15-65738686-A-G
• rs10519304
• NM_001320835.1:c.801+20T>C

Variant summary

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

The NM_001320835.1(DENND4A):​c.801+20T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0599 in 1,578,928 control chromosomes in the GnomAD database, including 3,181 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 0.067 (366 hom., cov: 32)
  • Exomes 𝑓: 0.059 (2815 hom.)
• Consequence: DENND4A NM_001320835.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0740

Genes affected

DENND4A (HGNC:24321): (DENN domain containing 4A) This gene encodes a DENN domain-containing protein that may function as a guanine nucleotide exchange factor that specifically activates ras-related protein Rab-10. This protein also contains a interferon stimulated response element-binding domain and may be involved in regulating the v-myc avian myelocytomatosis viral (MYC) oncogene. Alternate splicing results in multiple transcript variants. A pseudogene of this gene is found on chromosome 8. [provided by RefSeq, Mar 2016]

RAB11A (HGNC:9760): (RAB11A, member RAS oncogene family) The protein encoded by this gene belongs to the Rab family of the small GTPase superfamily. It is associated with both constitutive and regulated secretory pathways, and may be involved in protein transport. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2011]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.101 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DENND4A	NM_001320835.1	c.801+20T>C		intron_variant	Intron 6 of 32	ENST00000443035.8	NP_001307764.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DENND4A	ENST00000443035.8	c.801+20T>C		intron_variant	Intron 6 of 32	1	NM_001320835.1	ENSP00000391167.4

Frequencies

GnomAD3 genomes AF: 0.0670 AC: 10185 AN: 152124 Hom.: 367 Cov.: 32

Gnomad AFR AF: 0.103

Gnomad AMI AF: 0.0559

Gnomad AMR AF: 0.0440

Gnomad ASJ AF: 0.0652

Gnomad EAS AF: 0.0432

Gnomad SAS AF: 0.0567

Gnomad FIN AF: 0.0345

Gnomad MID AF: 0.0828

Gnomad NFE AF: 0.0576

Gnomad OTH AF: 0.0741

GnomAD3 exomes AF: 0.0536 AC: 12136 AN: 226580 Hom.: 394 AF XY: 0.0543 AC XY: 6683 AN XY: 123148

Gnomad AFR exome AF: 0.104

Gnomad AMR exome AF: 0.0292

Gnomad ASJ exome AF: 0.0719

Gnomad EAS exome AF: 0.0443

Gnomad SAS exome AF: 0.0599

Gnomad FIN exome AF: 0.0320

Gnomad NFE exome AF: 0.0553

Gnomad OTH exome AF: 0.0578

GnomAD4 exome AF: 0.0592 AC: 84412 AN: 1426686 Hom.: 2815 Cov.: 29 AF XY: 0.0591 AC XY: 41827 AN XY: 708064

Gnomad4 AFR exome AF: 0.107

Gnomad4 AMR exome AF: 0.0309

Gnomad4 ASJ exome AF: 0.0683

Gnomad4 EAS exome AF: 0.0436

Gnomad4 SAS exome AF: 0.0592

Gnomad4 FIN exome AF: 0.0311

Gnomad4 NFE exome AF: 0.0601

Gnomad4 OTH exome AF: 0.0637

GnomAD4 genome AF: 0.0669 AC: 10189 AN: 152242 Hom.: 366 Cov.: 32 AF XY: 0.0657 AC XY: 4889 AN XY: 74450

Gnomad4 AFR AF: 0.103

Gnomad4 AMR AF: 0.0440

Gnomad4 ASJ AF: 0.0652

Gnomad4 EAS AF: 0.0429

Gnomad4 SAS AF: 0.0565

Gnomad4 FIN AF: 0.0345

Gnomad4 NFE AF: 0.0575

Gnomad4 OTH AF: 0.0733

Alfa AF: 0.0658 Hom.: 104

Bravo AF: 0.0691

Asia WGS AF: 0.0490 AC: 171 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	6.8
DANN	Benign	0.70
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs10519304; hg19: chr15-66031024;