chr16-15643753-T-A

Variant names:

• chr16-15643753-T-A
• rs752993685
• ENST00000396355.5:c.-340T>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001143979.2(NDE1):​c.-340T>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 0.000103 in 213,612 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: NDE1 NM_001143979.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.265
• Publications: 0 publications found

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]

NDE1 Gene-Disease associations (from GenCC):

• lissencephaly 4

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: PanelApp Australia, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
• hydranencephaly

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• microlissencephaly

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• NDE1-related microhydranencephaly

  Inheritance: Unknown, AR Classification: SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NDE1	NM_001143979.2	c.-340T>A		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 10		NP_001137451.1
NDE1	XM_006720897.5	c.-122T>A		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 8		XP_006720960.1
NDE1	XM_047434258.1	c.-122T>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	ENST00000396355.5	c.-340T>A		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 10	1		ENSP00000379643.1
NDE1	ENST00000396355.5	c.-340T>A		5_prime_UTR_variant	Exon 1 of 10	1		ENSP00000379643.1
NDE1	ENST00000674888.1	n.-218T>A		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 10			ENSP00000501936.1

Frequencies

GnomAD3 genomes AF: 0.0000920 AC: 14 AN: 152136 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.000479

GnomAD4 exome AF: 0.000130 AC: 8 AN: 61476 Hom.: 0 Cov.: 0 AF XY: 0.000149 AC XY: 5 AN XY: 33470

African (AFR) AF: 0.00 AC: 0 AN: 290

American (AMR) AF: 0.00 AC: 0 AN: 308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1358

East Asian (EAS) AF: 0.00 AC: 0 AN: 214

South Asian (SAS) AF: 0.00 AC: 0 AN: 13884

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 3952

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 234

European-Non Finnish (NFE) AF: 0.000211 AC: 8 AN: 37864

Other (OTH) AF: 0.00 AC: 0 AN: 3372

GnomAD4 genome AF: 0.0000920 AC: 14 AN: 152136 Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5 AN XY: 74334

African (AFR) AF: 0.0000241 AC: 1 AN: 41442

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 68012

Other (OTH) AF: 0.000479 AC: 1 AN: 2088

Alfa AF: 0.0000693 Hom.: 0

Bravo AF: 0.0000718

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Lissencephaly 4 Uncertain:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	7.8
DANN	Benign	0.77
PhyloP100		-0.27
PromoterAI		-0.024	Neutral

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

Other links and lift over

dbSNP: rs752993685; hg19: chr16-15737610;