16-15643320-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BS1 BS2

The ENST00000396355.5(NDE1):c.-773G>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 0.00206 in 473,166 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0024 (4 hom.)
• Consequence: NDE1 ENST00000396355.5 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.09

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).
• BP6: Variant 16-15643320-G-A is Benign according to our data. Variant chr16-15643320-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 318016.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00126 (192/152194) while in subpopulation SAS AF= 0.00311 (15/4826). AF 95% confidence interval is 0.00192. There are 0 homozygotes in gnomad4. There are 92 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MIR484	NR_030159.1	n.27G>A		non_coding_transcript_exon_variant	1/1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NDE1	ENST00000396355.5	c.-773G>A		5_prime_UTR_variant	1/10	1		P1
MIR484	ENST00000606601.3	n.27G>A		mature_miRNA_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.00126 AC: 192 AN: 152076 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000786

Gnomad ASJ AF: 0.0107

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00311

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00163

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00202 AC: 327 AN: 162188 Hom.: 2 AF XY: 0.00232 AC XY: 205 AN XY: 88384

Gnomad AFR exome AF: 0.000388

Gnomad AMR exome AF: 0.000528

Gnomad ASJ exome AF: 0.00738

Gnomad EAS exome AF: 0.0000941

Gnomad SAS exome AF: 0.00473

Gnomad FIN exome AF: 0.0000594

Gnomad NFE exome AF: 0.00192

Gnomad OTH exome AF: 0.00231

GnomAD4 exome AF: 0.00244 AC: 783 AN: 320972 Hom.: 4 Cov.: 0 AF XY: 0.00277 AC XY: 508 AN XY: 183274

Gnomad4 AFR exome AF: 0.000141

Gnomad4 AMR exome AF: 0.000575

Gnomad4 ASJ exome AF: 0.00854

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00532

Gnomad4 FIN exome AF: 0.0000695

Gnomad4 NFE exome AF: 0.00178

Gnomad4 OTH exome AF: 0.00310

GnomAD4 genome AF: 0.00126 AC: 192 AN: 152194 Hom.: 0 Cov.: 32 AF XY: 0.00124 AC XY: 92 AN XY: 74408

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.000785

Gnomad4 ASJ AF: 0.0107

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00311

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.00163

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00243 Hom.: 1

Bravo AF: 0.00124

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Lissencephaly 4 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
Cadd	Benign	20
Dann	Benign	0.94

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: rs376603273; hg19: chr16-15737177;