16-15643558-C-A

Variant names:

• chr16-15643558-C-A
• rs187630586
• ENST00000396355:c.-535C>A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 2P and 10B. PM2 BP4_Strong BP6_Moderate BS1

The NM_001143979.2(NDE1):​c.-535C>A variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000495 in 337,086 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00075 (1 hom., cov: 31)
  • Exomes 𝑓: 0.00029 (0 hom.)
• Consequence: NDE1 NM_001143979.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.781

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 -8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 16-15643558-C-A is Benign according to our data. Variant chr16-15643558-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 318024.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000751 (114/151856) while in subpopulation EAS AF= 0.017 (88/5178). AF 95% confidence interval is 0.0141. There are 1 homozygotes in gnomad4. There are 53 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NDE1	NM_001143979.2	c.-535C>A		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 10		NP_001137451.1
NDE1	XM_006720897.5	c.-317C>A		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 8		XP_006720960.1
NDE1	XM_047434258.1	c.-317C>A		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 8		XP_047290214.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NDE1	ENST00000396355	c.-535C>A		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 10	1		ENSP00000379643.1
NDE1	ENST00000396355	c.-535C>A		5_prime_UTR_variant	Exon 1 of 10	1		ENSP00000379643.1
NDE1	ENST00000674888.1	n.-413C>A		upstream_gene_variant				ENSP00000501936.1
MIR484	ENST00000606601.3	n.*186C>A		downstream_gene_variant		6

Frequencies

GnomAD3 genomes AF: 0.000751 AC: 114 AN: 151746 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.000146

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0170

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00287

GnomAD4 exome AF: 0.000286 AC: 53 AN: 185230 Hom.: 0 Cov.: 0 AF XY: 0.000317 AC XY: 34 AN XY: 107272

Gnomad4 AFR exome AF: 0.00157

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0198

Gnomad4 SAS exome AF: 0.0000987

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000927

Gnomad4 OTH exome AF: 0.00174

GnomAD4 genome AF: 0.000751 AC: 114 AN: 151856 Hom.: 1 Cov.: 31 AF XY: 0.000714 AC XY: 53 AN XY: 74204

Gnomad4 AFR AF: 0.000145

Gnomad4 AMR AF: 0.000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0170

Gnomad4 SAS AF: 0.000623

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.0132 Hom.: 6

Bravo AF: 0.000873

Asia WGS AF: 0.0110 AC: 39 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Lissencephaly 4 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	-0.79
CADD	Benign	1.9
DANN	Benign	0.54

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: rs187630586; hg19: chr16-15737415;