rs146284370

chr16-15696785-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2 BP4_Strong BP6 BS1

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:3
• Conservation: PhyloP100: 1.28

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 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: {Uncertain_significance=4, Likely_benign=2, 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. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NDE1	NM_017668.3	c.872C>T	p.Ser291Phe	missense_variant	8/9	ENST00000396354.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NDE1	ENST00000396354.6	c.872C>T	p.Ser291Phe	missense_variant	8/9	1	NM_017668.3	P1

Frequencies

GnomAD3 genomes AF: 0.000545 AC: 83 AN: 152218 Hom.: 0 Cov.: 32

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.: 0 AF XY: 0.000626 AC XY: 85 AN XY: 135826

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.: 1 Cov.: 32 AF XY: 0.000527 AC XY: 383 AN XY: 727246

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: 84 AN: 152336 Hom.: 0 Cov.: 32 AF XY: 0.000416 AC XY: 31 AN XY: 74486

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: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000228 AC: 1

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000552 AC: 67

EpiCase AF: 0.00115

EpiControl AF: 0.000948

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Lissencephaly 4 Uncertain:2 Benign:1

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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 17, 2014	- -
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. -

not provided Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 16, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 01, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 09, 2023	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	T
BayesDel_noAF	Benign	-0.25
Cadd	Benign	19
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	N
M_CAP	Benign	0.0075	T
MetaRNN	Benign	0.019	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	M;M;.;.;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.39	T
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	T
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

Other links and lift over

dbSNP: rs146284370; hg19: chr16-15790642; COSMIC: COSV100707448; COSMIC: COSV100707448;