rs146418251

Variant names:

• chr16-15643555-AC-A
• rs146418251
• ENST00000396355:c.-535delC

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_001143979.2(NDE1):​c.-535delC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0111 in 324,396 control chromosomes in the GnomAD database, including 141 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.023 (141 hom., cov: 31)
  • Exomes 𝑓: 0.0010 (0 hom.)
• Consequence: NDE1 NM_001143979.2 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.15

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 -10 ACMG points.

• BP6: Variant 16-15643555-AC-A is Benign according to our data. Variant chr16-15643555-AC-A is described in ClinVar as [Likely_benign]. Clinvar id is 318023.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0782 is higher than 0.05.

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NDE1	ENST00000396355	c.-535delC		5_prime_UTR_variant	Exon 1 of 10	1		ENSP00000379643.1
NDE1	ENST00000674888.1	n.-415delC		upstream_gene_variant				ENSP00000501936.1
MIR484	ENST00000606601.3	n.*184delC		downstream_gene_variant		6

Frequencies

GnomAD3 genomes AF: 0.0233 AC: 3430 AN: 146942 Hom.: 141 Cov.: 31

Gnomad AFR AF: 0.0806

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00964

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000431

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000465

Gnomad OTH AF: 0.0171

GnomAD4 exome AF: 0.00101 AC: 179 AN: 177406 Hom.: 0 Cov.: 0 AF XY: 0.000797 AC XY: 82 AN XY: 102948

Gnomad4 AFR exome AF: 0.0644

Gnomad4 AMR exome AF: 0.00529

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000152

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000370

Gnomad4 OTH exome AF: 0.00512

GnomAD4 genome AF: 0.0233 AC: 3432 AN: 146990 Hom.: 141 Cov.: 31 AF XY: 0.0229 AC XY: 1635 AN XY: 71502

Gnomad4 AFR AF: 0.0805

Gnomad4 AMR AF: 0.00956

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000433

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000465

Gnomad4 OTH AF: 0.0170

Alfa AF: 0.0177 Hom.: 11

Bravo AF: 0.0254

Asia WGS AF: 0.00404 AC: 14 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Lissencephaly, Recessive Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

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: rs146418251; hg19: chr16-15737412;