16-15643570-C-CT

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BS1_Supporting

The NM_001143979.2(NDE1):c.-512dupT variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0187 in 260,198 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00086 ( 0 hom., cov: 31)

Exomes 𝑓: 0.042 ( 0 hom. )

Consequence

NDE1
NM_001143979.2 5_prime_UTR

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.176

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:

MIR484 (HGNC:32341): (microRNA 484) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

MIR484 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Variant has high frequency in the NFE (0.0424) population. However there is too low homozygotes in high coverage region: (expected more than 22, got 0).

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00086 (126/146476) while in subpopulation AMR AF = 0.00136 (20/14664). AF 95% confidence interval is 0.000903. There are 0 homozygotes in GnomAd4. There are 61 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position FAILED quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	Protein	UniProt
NDE1	NM_001143979.2 link	c.-512dupT	5_prime_UTR_variant	Exon 1 of 10	NP_001137451.1	Q9NXR1-2X5DR54
NDE1	XM_006720897.5 link	c.-294dupT	5_prime_UTR_variant	Exon 1 of 8	XP_006720960.1
NDE1	XM_047434258.1 link	c.-294dupT	5_prime_UTR_variant	Exon 1 of 8	XP_047290214.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	Protein	UniProt
NDE1	ENST00000396355 link	c.-512dupT	5_prime_UTR_variant	Exon 1 of 10	1	ENSP00000379643.1	Q9NXR1-2
NDE1	ENST00000674888.1 link	n.-401_-400insT	upstream_gene_variant			ENSP00000501936.1	Q9NXR1-2
MIR484	ENST00000606601.3 link	n.198_199insT	downstream_gene_variant		6

Frequencies

GnomAD3 genomes

AF:

0.000854

AC:

125

AN:

146424

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000923

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00137

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000593

Gnomad SAS

AF:

0.00107

Gnomad FIN

AF:

0.000768

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000769

Gnomad OTH

AF:

0.00101

GnomAD4 exome

AF:

0.0418

AC:

4752

AN:

113722

Hom.:

Cov.:

AF XY:

0.0409

AC XY:

2686

AN XY:

65746

show subpopulations

Gnomad4 AFR exome

AF:

0.0385

AC:

AN:

728

Gnomad4 AMR exome

AF:

0.0331

AC:

AN:

1632

Gnomad4 ASJ exome

AF:

0.0386

AC:

129

AN:

3342

Gnomad4 EAS exome

AF:

0.0433

AC:

AN:

786

Gnomad4 SAS exome

AF:

0.0398

AC:

1009

AN:

25320

Gnomad4 FIN exome

AF:

0.0328

AC:

261

AN:

7946

Gnomad4 NFE exome

AF:

0.0437

AC:

2966

AN:

67846

Gnomad4 Remaining exome

AF:

0.0454

AC:

243

AN:

5358

⚠️ The allele balance in gnomAD4 Exomes is highly skewed (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Heterozygous variant carriers

614

1228

1843

2457

3071

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Variant carriers

<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:

0.000860

AC:

126

AN:

146476

Hom.:

Cov.:

AF XY:

0.000857

AC XY:

AN XY:

71208

show subpopulations

Gnomad4 AFR

AF:

0.000946

AC:

0.00094598

AN:

0.00094598

Gnomad4 AMR

AF:

0.00136

AC:

0.00136388

AN:

0.00136388

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.000595

AC:

0.00059453

AN:

0.00059453

Gnomad4 SAS

AF:

0.00108

AC:

0.00107666

AN:

0.00107666

Gnomad4 FIN

AF:

0.000768

AC:

0.000768218

AN:

0.000768218

Gnomad4 NFE

AF:

0.000770

AC:

0.000769602

AN:

0.000769602

Gnomad4 OTH

AF:

0.000995

AC:

0.000995025

AN:

0.000995025

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Variant carriers

<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:

0.0000541

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Lissencephaly, Recessive

Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Mutation Taster

=300/0

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

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