16-15696785-C-T

Position:

chr16-15696785-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2BP4_StrongBP6BS1

The NM_017668.3(NDE1):c.872C>T(p.Ser291Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000515 in 1,614,226 control chromosomes in the GnomAD database, including 1 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00055 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00051 ( 1 hom. )

Consequence

NDE1
NM_017668.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:3

Conservation

PhyloP100: 1.28

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.019272298).

BP6

Variant 16-15696785-C-T is Benign according to our data. Variant chr16-15696785-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 159020.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=4, Benign=1}.

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000551 (84/152336) while in subpopulation AMR AF= 0.00164 (25/15290). AF 95% confidence interval is 0.00114. There are 0 homozygotes in gnomad4. There are 31 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NDE1	NM_017668.3 linkuse as main transcript	c.872C>T	p.Ser291Phe	missense_variant	8/9	ENST00000396354.6	NP_060138.1	Q9NXR1-2X5DR54

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NDE1	ENST00000396354.6 linkuse as main transcript	c.872C>T	p.Ser291Phe	missense_variant	8/9	1	NM_017668.3	ENSP00000379642.1		Q9NXR1-2

Frequencies

GnomAD3 genomes

AF:

0.000545

AC:

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00164

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000620

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000647

Gnomad OTH

AF:

0.000955

GnomAD3 exomes

AF:

0.000513

AC:

129

AN:

251306

Hom.:

AF XY:

0.000626

AC XY:

AN XY:

135826

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000434

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000784

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000748

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.000512

AC:

748

AN:

1461890

Hom.:

Cov.:

AF XY:

0.000527

AC XY:

383

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.000179

Gnomad4 AMR exome

AF:

0.000470

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000869

Gnomad4 FIN exome

AF:

0.0000374

Gnomad4 NFE exome

AF:

0.000522

Gnomad4 OTH exome

AF:

0.000679

GnomAD4 genome

AF:

0.000551

AC:

AN:

152336

Hom.:

Cov.:

AF XY:

0.000416

AC XY:

AN XY:

74486

show subpopulations

Gnomad4 AFR

AF:

0.000168

Gnomad4 AMR

AF:

0.00164

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000621

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.000661

Gnomad4 OTH

AF:

0.000945

Alfa

AF:

0.0253

Hom.:

841

Bravo

AF:

0.000582

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000228

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000552

AC:

EpiCase

AF:

0.00115

EpiControl

AF:

0.000948

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Lissencephaly 4

Uncertain:2Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 17, 2014	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 01, 2017	Likely pathogenicity based on finding it once in our laboratory in trans with a 16p13.11 deletion in a 1-year-old male with global delays, hypotonia, poor weight gain, optic atrophy, abnormal auditory brainstem responses, strabismus, brachycephaly. Heterozygotes are expected to be asymptomatic carriers. -

not provided

Uncertain:1Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 16, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 01, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 29, 2024	See Variant Classification Assertion Criteria. -

NDE1-related microhydranencephaly;C3151461:Lissencephaly 4

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Intellectual disability

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Jan 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.25

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.12

T;T;T;T;T

Eigen

Benign

-0.31

Eigen_PC

Benign

-0.34

FATHMM_MKL

Benign

0.44

LIST_S2

Uncertain

0.88

.;D;D;D;D

M_CAP

Benign

0.0075

MetaRNN

Benign

0.019

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.2

M;M;.;.;.

PrimateAI

Benign

0.39

PROVEAN

Benign

-1.4

N;N;.;.;.

REVEL

Benign

0.10

Sift

Uncertain

0.012

D;D;.;.;.

Sift4G

Uncertain

0.048

D;D;D;D;D

Polyphen

0.27

B;B;.;.;.

Vest4

0.55

MVP

0.69

MPC

0.096

ClinPred

0.035

GERP RS

3.6

Varity_R

0.076

gMVP

0.46

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over