15-65778355-C-T

Variant names:

• chr15-65778355-C-T
• rs2572207
• NM_001320835.1:c.-102+13655G>A

Variant summary

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

The NM_001320835.1(DENND4A):​c.-102+13655G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.316 in 147,154 control chromosomes in the GnomAD database, including 8,117 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 0.32 (8117 hom., cov: 28)
• Consequence: DENND4A NM_001320835.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.417
• Publications: 30 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=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.764 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DENND4A	NM_001320835.1	c.-102+13655G>A		intron_variant	Intron 1 of 32	ENST00000443035.8	NP_001307764.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DENND4A	ENST00000443035.8	c.-102+13655G>A		intron_variant	Intron 1 of 32	1	NM_001320835.1	ENSP00000391167.4

Frequencies

GnomAD3 genomes AF: 0.316 AC: 46486 AN: 147030 Hom.: 8108 Cov.: 28

Gnomad AFR AF: 0.390

Gnomad AMI AF: 0.161

Gnomad AMR AF: 0.278

Gnomad ASJ AF: 0.215

Gnomad EAS AF: 0.785

Gnomad SAS AF: 0.410

Gnomad FIN AF: 0.319

Gnomad MID AF: 0.252

Gnomad NFE AF: 0.245

Gnomad OTH AF: 0.301

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

GnomAD4 genome AF: 0.316 AC: 46525 AN: 147154 Hom.: 8117 Cov.: 28 AF XY: 0.323 AC XY: 23273 AN XY: 71964

African (AFR) AF: 0.390 AC: 15586 AN: 39956

American (AMR) AF: 0.277 AC: 4079 AN: 14720

Ashkenazi Jewish (ASJ) AF: 0.215 AC: 726 AN: 3370

East Asian (EAS) AF: 0.784 AC: 3983 AN: 5080

South Asian (SAS) AF: 0.409 AC: 1896 AN: 4638

European-Finnish (FIN) AF: 0.319 AC: 3253 AN: 10190

Middle Eastern (MID) AF: 0.252 AC: 70 AN: 278

European-Non Finnish (NFE) AF: 0.245 AC: 16180 AN: 66036

Other (OTH) AF: 0.305 AC: 609 AN: 1998

Alfa AF: 0.310 Hom.: 4695

Bravo AF: 0.310

Asia WGS AF: 0.519 AC: 1805 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.2
DANN	Benign	0.29
PhyloP100		-0.42
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: rs2572207; hg19: chr15-66070693;