rs10519304

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 7 publications found

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]

RAB11A Gene-Disease associations (from GenCC):

• neurodevelopmental disorder

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics
• autosomal dominant non-syndromic intellectual disability

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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

GnomAD2 exomes AF: 0.0536 AC: 12136 AN: 226580 AF XY: 0.0543

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 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

African (AFR) AF: 0.107 AC: 3432 AN: 32034

American (AMR) AF: 0.0309 AC: 1178 AN: 38100

Ashkenazi Jewish (ASJ) AF: 0.0683 AC: 1707 AN: 25004

East Asian (EAS) AF: 0.0436 AC: 1695 AN: 38872

South Asian (SAS) AF: 0.0592 AC: 4705 AN: 79460

European-Finnish (FIN) AF: 0.0311 AC: 1644 AN: 52842

Middle Eastern (MID) AF: 0.0698 AC: 393 AN: 5630

European-Non Finnish (NFE) AF: 0.0601 AC: 65903 AN: 1095834

Other (OTH) AF: 0.0637 AC: 3755 AN: 58910

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

African (AFR) AF: 0.103 AC: 4286 AN: 41538

American (AMR) AF: 0.0440 AC: 672 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0652 AC: 226 AN: 3466

East Asian (EAS) AF: 0.0429 AC: 223 AN: 5194

South Asian (SAS) AF: 0.0565 AC: 273 AN: 4830

European-Finnish (FIN) AF: 0.0345 AC: 366 AN: 10616

Middle Eastern (MID) AF: 0.0822 AC: 24 AN: 292

European-Non Finnish (NFE) AF: 0.0575 AC: 3913 AN: 67994

Other (OTH) AF: 0.0733 AC: 155 AN: 2114

Alfa AF: 0.0680 Hom.: 131

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
PhyloP100		0.074
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs10519304; hg19: chr15-66031024;