16-15643570-C-CT

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BS1_Supporting

The ENST00000396355.5(NDE1):c.-512dup variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0187 in 260,198 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00086 (0 hom., cov: 31)
  • Exomes 𝑓: 0.042 (0 hom.)
• Consequence: NDE1 ENST00000396355.5 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.176

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00086 (126/146476) while in subpopulation AMR AF= 0.00136 (20/14664). AF 95% confidence interval is 0.000903. There are 0 homozygotes in gnomad4. There are 61 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NDE1	NM_001143979.2	c.-512dup		5_prime_UTR_variant	1/10
NDE1	XM_006720897.5	c.-294dup		5_prime_UTR_variant	1/8
NDE1	XM_047434258.1	c.-294dup		5_prime_UTR_variant	1/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NDE1	ENST00000396355.5	c.-512dup		5_prime_UTR_variant	1/10	1		P1
NDE1	ENST00000674888.1			upstream_gene_variant

Frequencies

GnomAD3 genomes AF: 0.000854 AC: 125 AN: 146424 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000923

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00137

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000593

Gnomad SAS AF: 0.00107

Gnomad FIN AF: 0.000768

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000769

Gnomad OTH AF: 0.00101

GnomAD4 exome AF: 0.0418 AC: 4752 AN: 113722 Hom.: 0 Cov.: 0 AF XY: 0.0409 AC XY: 2686 AN XY: 65746

Gnomad4 AFR exome AF: 0.0385

Gnomad4 AMR exome AF: 0.0331

Gnomad4 ASJ exome AF: 0.0386

Gnomad4 EAS exome AF: 0.0433

Gnomad4 SAS exome AF: 0.0398

Gnomad4 FIN exome AF: 0.0328

Gnomad4 NFE exome AF: 0.0437

Gnomad4 OTH exome AF: 0.0454

GnomAD4 genome AF: 0.000860 AC: 126 AN: 146476 Hom.: 0 Cov.: 31 AF XY: 0.000857 AC XY: 61 AN XY: 71208

Gnomad4 AFR AF: 0.000946

Gnomad4 AMR AF: 0.00136

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000595

Gnomad4 SAS AF: 0.00108

Gnomad4 FIN AF: 0.000768

Gnomad4 NFE AF: 0.000770

Gnomad4 OTH AF: 0.000995

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Lissencephaly, Recessive Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

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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: rs796579453; hg19: chr16-15737427;