chr15-65759007-C-T

Variant names:

• chr15-65759007-C-T
• rs6494537
• NM_001320835.1:c.-23+2353G>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.-23+2353G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.561 in 152,044 control chromosomes in the GnomAD database, including 26,364 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 (26364 hom., cov: 32)
• Consequence: DENND4A NM_001320835.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.00
• Publications: 33 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=-0.86).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.82 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DENND4A	NM_001320835.1	c.-23+2353G>A		intron_variant	Intron 2 of 32	ENST00000443035.8	NP_001307764.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DENND4A	ENST00000443035.8	c.-23+2353G>A		intron_variant	Intron 2 of 32	1	NM_001320835.1	ENSP00000391167.4

Frequencies

GnomAD3 genomes AF: 0.560 AC: 85140 AN: 151926 Hom.: 26319 Cov.: 32

Gnomad AFR AF: 0.827

Gnomad AMI AF: 0.297

Gnomad AMR AF: 0.449

Gnomad ASJ AF: 0.406

Gnomad EAS AF: 0.807

Gnomad SAS AF: 0.568

Gnomad FIN AF: 0.464

Gnomad MID AF: 0.503

Gnomad NFE AF: 0.431

Gnomad OTH AF: 0.539

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

GnomAD4 genome AF: 0.561 AC: 85252 AN: 152044 Hom.: 26364 Cov.: 32 AF XY: 0.560 AC XY: 41587 AN XY: 74306

African (AFR) AF: 0.827 AC: 34318 AN: 41482

American (AMR) AF: 0.449 AC: 6868 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.406 AC: 1410 AN: 3470

East Asian (EAS) AF: 0.807 AC: 4183 AN: 5184

South Asian (SAS) AF: 0.566 AC: 2724 AN: 4816

European-Finnish (FIN) AF: 0.464 AC: 4893 AN: 10542

Middle Eastern (MID) AF: 0.503 AC: 148 AN: 294

European-Non Finnish (NFE) AF: 0.431 AC: 29295 AN: 67956

Other (OTH) AF: 0.542 AC: 1143 AN: 2108

Alfa AF: 0.471 Hom.: 58883

Bravo AF: 0.572

Asia WGS AF: 0.674 AC: 2343 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.1
DANN	Benign	0.61
PhyloP100		-1.0
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: rs6494537; hg19: chr15-66051345;