16-15677865-C-T

Variant names:

• chr16-15677865-C-T
• rs201587506
• NM_017668.3:c.302C>T

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BS1_Supporting BS2

The NM_017668.3(NDE1):​c.302C>T​(p.Ala101Val) variant causes a missense change. The variant allele was found at a frequency of 0.000205 in 1,613,952 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00021 (3 hom.)
• Consequence: NDE1 NM_017668.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:8
• Conservation: PhyloP100: 4.91
• Publications: 2 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: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07110211).
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.000206 (301/1461882) while in subpopulation MID AF = 0.00503 (29/5768). AF 95% confidence interval is 0.0036. There are 3 homozygotes in GnomAdExome4. There are 159 alleles in the male GnomAdExome4 subpopulation. Median coverage is 34. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 3 AR,Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017668.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDE1	NM_017668.3	MANE Select	c.302C>T	p.Ala101Val	missense	Exon 4 of 9	NP_060138.1
	NDE1	NM_001143979.2		c.302C>T	p.Ala101Val	missense	Exon 5 of 10	NP_001137451.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDE1	ENST00000396354.6	TSL:1 MANE Select	c.302C>T	p.Ala101Val	missense	Exon 4 of 9	ENSP00000379642.1
	NDE1	ENST00000396355.5	TSL:1	c.302C>T	p.Ala101Val	missense	Exon 5 of 10	ENSP00000379643.1
	NDE1	ENST00000577101.6	TSL:4	c.302C>T	p.Ala101Val	missense	Exon 3 of 9	ENSP00000461729.2

Frequencies

GnomAD3 genomes AF: 0.000197 AC: 30 AN: 152070 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000657

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.000275 AC: 69 AN: 251338 AF XY: 0.000280

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00198

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000246

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000206 AC: 301 AN: 1461882 Hom.: 3 Cov.: 34 AF XY: 0.000219 AC XY: 159 AN XY: 727246

African (AFR) AF: 0.000358 AC: 12 AN: 33480

American (AMR) AF: 0.000201 AC: 9 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00187 AC: 49 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000406 AC: 35 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00503 AC: 29 AN: 5768

European-Non Finnish (NFE) AF: 0.000123 AC: 137 AN: 1112002

Other (OTH) AF: 0.000497 AC: 30 AN: 60396

GnomAD4 genome AF: 0.000197 AC: 30 AN: 152070 Hom.: 0 Cov.: 32 AF XY: 0.000189 AC XY: 14 AN XY: 74270

African (AFR) AF: 0.0000241 AC: 1 AN: 41416

American (AMR) AF: 0.0000657 AC: 1 AN: 15222

Ashkenazi Jewish (ASJ) AF: 0.00231 AC: 8 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000265 AC: 18 AN: 68022

Other (OTH) AF: 0.000956 AC: 2 AN: 2092

Alfa AF: 0.000296 Hom.: 0

Bravo AF: 0.000212

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000231 AC: 28

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000545

EpiControl AF: 0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:5

Dec 06, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 101 of the NDE1 protein (p.Ala101Val). This variant is present in population databases (rs201587506, gnomAD 0.2%). This variant has not been reported in the literature in individuals affected with NDE1-related conditions. ClinVar contains an entry for this variant (Variation ID: 287331). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt NDE1 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

May 12, 2016

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 05, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 21529752)

Oct 02, 2020

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: not provided

NDE1-related microhydranencephaly;C3151461:Lissencephaly 4 Uncertain:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Uncertain:1

May 09, 2016

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Lissencephaly 4 Uncertain:1

Jan 13, 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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.34
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.39	T
Eigen	Uncertain	0.23
Eigen_PC	Benign	0.22
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.0093	T
MetaRNN	Benign	0.071	T
MetaSVM	Benign	-0.66	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		4.9
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.098
Sift	Benign	0.064	T
Sift4G	Benign	0.21	T
Polyphen		1.0	D
Vest4		0.52
MVP		0.87
MPC		0.15
ClinPred		0.22	T
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.15
gMVP		0.71
Mutation Taster		=100/0	polymorphism

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: rs201587506; hg19: chr16-15771722; COSMIC: COSV61278736; COSMIC: COSV61278736;