rs113493697

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_017668.3(NDE1):c.572C>T(p.Thr191Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0108 in 1,614,118 control chromosomes in the GnomAD database, including 126 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0090 ( 16 hom., cov: 31)

Exomes 𝑓: 0.011 ( 110 hom. )

Consequence

NDE1
NM_017668.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 2.62

Publications

12 publications found

Variant links:

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: Labcorp Genetics (formerly Invitae), G2P, Laboratory for Molecular Medicine, Ambry Genetics
microcephaly with lissencephaly and/or hydranencephaly
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
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

NDE1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005299479).

BP6

Variant 16-15691192-C-T is Benign according to our data. Variant chr16-15691192-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 138430.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00903 (1375/152230) while in subpopulation NFE AF = 0.0157 (1065/68006). AF 95% confidence interval is 0.0149. There are 16 homozygotes in GnomAd4. There are 629 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 16 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDE1	NM_017668.3	MANE Select	c.572C>T	p.Thr191Ile	missense	Exon 6 of 9	NP_060138.1	Q9NXR1-2
	NDE1	NM_001143979.2		c.572C>T	p.Thr191Ile	missense	Exon 7 of 10	NP_001137451.1	Q9NXR1-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NDE1	ENST00000396354.6	TSL:1 MANE Select	c.572C>T	p.Thr191Ile	missense	Exon 6 of 9	ENSP00000379642.1	Q9NXR1-2
NDE1	ENST00000396355.5	TSL:1	c.572C>T	p.Thr191Ile	missense	Exon 7 of 10	ENSP00000379643.1	Q9NXR1-2
NDE1	ENST00000577101.6	TSL:4	c.572C>T	p.Thr191Ile	missense	Exon 5 of 9	ENSP00000461729.2	I3L522

Frequencies

GnomAD3 genomes

AF:

0.00903

AC:

1374

AN:

152112

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00208

Gnomad AMI

AF:

0.00439

Gnomad AMR

AF:

0.00584

Gnomad ASJ

AF:

0.0133

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00622

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0157

Gnomad OTH

AF:

0.00622

GnomAD2 exomes

AF:

0.00853

AC:

2143

AN:

251250

AF XY:

0.00829

show subpopulations

Gnomad AFR exome

AF:

0.00191

Gnomad AMR exome

AF:

0.00466

Gnomad ASJ exome

AF:

0.0132

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00670

Gnomad NFE exome

AF:

0.0143

Gnomad OTH exome

AF:

0.00653

GnomAD4 exome

AF:

0.0110

AC:

16073

AN:

1461888

Hom.:

110

Cov.:

AF XY:

0.0108

AC XY:

7856

AN XY:

727244

show subpopulations

African (AFR)

AF:

0.00176

AC:

AN:

33480

American (AMR)

AF:

0.00440

AC:

197

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0139

AC:

362

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000255

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00745

AC:

398

AN:

53418

Middle Eastern (MID)

AF:

0.00815

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0131

AC:

14517

AN:

1112008

Other (OTH)

AF:

0.00780

AC:

471

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

1009

2018

3027

4036

5045

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

532

1064

1596

2128

2660

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00903

AC:

1375

AN:

152230

Hom.:

Cov.:

AF XY:

0.00845

AC XY:

629

AN XY:

74424

show subpopulations

African (AFR)

AF:

0.00207

AC:

AN:

41548

American (AMR)

AF:

0.00583

AC:

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.0133

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.000207

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00622

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0157

AC:

1065

AN:

68006

Other (OTH)

AF:

0.00616

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

146

219

292

365

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0112

Hom.:

Bravo

AF:

0.00841

TwinsUK

AF:

0.0111

AC:

ALSPAC

AF:

0.0122

AC:

ESP6500AA

AF:

0.00296

AC:

ESP6500EA

AF:

0.0142

AC:

122

ExAC

AF:

0.00874

AC:

1061

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.0146

EpiControl

AF:

0.0127

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (6)

not specified (3)

Lissencephaly 4 (1)

NDE1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.41

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.16

Eigen

Benign

-0.046

Eigen_PC

Benign

0.11

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.85

MetaRNN

Benign

0.0053

MetaSVM

Benign

-0.89

MutationAssessor

Benign

2.0

PhyloP100

2.6

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-0.87

REVEL

Benign

0.042

Sift

Benign

0.097

Sift4G

Benign

0.22

Polyphen

0.064

Vest4

0.43

MVP

0.85

MPC

0.093

ClinPred

0.0080

GERP RS

5.6

PromoterAI

0.097

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.071

gMVP

0.59

Mutation Taster

=90/10

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over