16-15643418-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The ENST00000396355.5(NDE1):c.-675G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00655 in 468,038 control chromosomes in the GnomAD database, including 45 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0054 (12 hom., cov: 32)
  • Exomes 𝑓: 0.0071 (33 hom.)
• Consequence: NDE1 ENST00000396355.5 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0240

Genes affected

NDE1 (HGNC:17619): (nudE neurodevelopment protein 1) This gene encodes a member of the nuclear distribution E (NudE) family of proteins. The encoded protein is localized at the centrosome and interacts with other centrosome components as part of a multiprotein complex that regulates dynein function. This protein plays an essential role in microtubule organization, mitosis and neuronal migration. Mutations in this gene cause lissencephaly 4, a disorder characterized by lissencephaly, severe brain atrophy, microcephaly, and severe cognitive disability. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2012]

MIR484 (HGNC:32341): (microRNA 484) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 16-15643418-G-A is Benign according to our data. Variant chr16-15643418-G-A is described in ClinVar as [Benign]. Clinvar id is 318020.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00543 (827/152308) while in subpopulation SAS AF= 0.0251 (121/4824). AF 95% confidence interval is 0.0215. There are 12 homozygotes in gnomad4. There are 445 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MIR484	NR_030159.1			downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NDE1	ENST00000396355.5	c.-675G>A		5_prime_UTR_variant	1/10	1		P1
MIR484	ENST00000606601.3			downstream_gene_variant

Frequencies

GnomAD3 genomes AF: 0.00533 AC: 811 AN: 152190 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.00589

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0107

Gnomad ASJ AF: 0.00864

Gnomad EAS AF: 0.00732

Gnomad SAS AF: 0.0251

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00278

Gnomad OTH AF: 0.00860

GnomAD3 exomes AF: 0.00728 AC: 1125 AN: 154572 Hom.: 12 AF XY: 0.00873 AC XY: 730 AN XY: 83596

Gnomad AFR exome AF: 0.00543

Gnomad AMR exome AF: 0.00499

Gnomad ASJ exome AF: 0.00841

Gnomad EAS exome AF: 0.0118

Gnomad SAS exome AF: 0.0250

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00330

Gnomad OTH exome AF: 0.00425

GnomAD4 exome AF: 0.00709 AC: 2237 AN: 315730 Hom.: 33 Cov.: 0 AF XY: 0.00886 AC XY: 1600 AN XY: 180544

Gnomad4 AFR exome AF: 0.00654

Gnomad4 AMR exome AF: 0.00448

Gnomad4 ASJ exome AF: 0.00780

Gnomad4 EAS exome AF: 0.0111

Gnomad4 SAS exome AF: 0.0225

Gnomad4 FIN exome AF: 0.000140

Gnomad4 NFE exome AF: 0.00291

Gnomad4 OTH exome AF: 0.00672

GnomAD4 genome AF: 0.00543 AC: 827 AN: 152308 Hom.: 12 Cov.: 32 AF XY: 0.00598 AC XY: 445 AN XY: 74472

Gnomad4 AFR AF: 0.00592

Gnomad4 AMR AF: 0.0107

Gnomad4 ASJ AF: 0.00864

Gnomad4 EAS AF: 0.00733

Gnomad4 SAS AF: 0.0251

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.00278

Gnomad4 OTH AF: 0.0156

Alfa AF: 0.00394 Hom.: 0

Bravo AF: 0.00525

Asia WGS AF: 0.0280 AC: 96 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Lissencephaly 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
Cadd	Benign	14
Dann	Benign	0.93

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: rs34560499; hg19: chr16-15737275;