rs587781094

chr16-15696750-C-TchrNT_187607.1-1354760-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_017668.3(NDE1):c.837C>T(p.Tyr279=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0353 in 1,614,186 control chromosomes in the GnomAD database, including 1,129 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.027 (75 hom., cov: 32)
  • Exomes 𝑓: 0.036 (1054 hom.)
• Consequence: NDE1 NM_017668.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.69

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 16-15696750-C-T is Benign according to our data. Variant chr16-15696750-C-T is described in ClinVar as [Benign]. Clinvar id is 138431.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-15696750-C-T is described in Lovd as [Benign]. Variant chr16-15696750-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-1.69 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0268 (4074/152296) while in subpopulation NFE AF= 0.0411 (2794/68020). AF 95% confidence interval is 0.0398. There are 75 homozygotes in gnomad4. There are 1916 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 75 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NDE1	NM_017668.3	c.837C>T	p.Tyr279=	synonymous_variant	8/9	ENST00000396354.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NDE1	ENST00000396354.6	c.837C>T	p.Tyr279=	synonymous_variant	8/9	1	NM_017668.3	P1

Frequencies

GnomAD3 genomes AF: 0.0268 AC: 4078 AN: 152178 Hom.: 75 Cov.: 32

Gnomad AFR AF: 0.00743

Gnomad AMI AF: 0.0274

Gnomad AMR AF: 0.0270

Gnomad ASJ AF: 0.0274

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0106

Gnomad FIN AF: 0.0299

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0411

Gnomad OTH AF: 0.0306

GnomAD3 exomes AF: 0.0285 AC: 7174 AN: 251386 Hom.: 128 AF XY: 0.0293 AC XY: 3975 AN XY: 135868

Gnomad AFR exome AF: 0.00560

Gnomad AMR exome AF: 0.0223

Gnomad ASJ exome AF: 0.0222

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0161

Gnomad FIN exome AF: 0.0309

Gnomad NFE exome AF: 0.0415

Gnomad OTH exome AF: 0.0331

GnomAD4 exome AF: 0.0362 AC: 52862 AN: 1461890 Hom.: 1054 Cov.: 32 AF XY: 0.0357 AC XY: 25988 AN XY: 727248

Gnomad4 AFR exome AF: 0.00570

Gnomad4 AMR exome AF: 0.0222

Gnomad4 ASJ exome AF: 0.0251

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.0152

Gnomad4 FIN exome AF: 0.0308

Gnomad4 NFE exome AF: 0.0413

Gnomad4 OTH exome AF: 0.0330

GnomAD4 genome AF: 0.0268 AC: 4074 AN: 152296 Hom.: 75 Cov.: 32 AF XY: 0.0257 AC XY: 1916 AN XY: 74466

Gnomad4 AFR AF: 0.00741

Gnomad4 AMR AF: 0.0269

Gnomad4 ASJ AF: 0.0274

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0106

Gnomad4 FIN AF: 0.0299

Gnomad4 NFE AF: 0.0411

Gnomad4 OTH AF: 0.0303

Alfa AF: 0.0381 Hom.: 216

Bravo AF: 0.0257

Asia WGS AF: 0.00433 AC: 15 AN: 3478

EpiCase AF: 0.0401

EpiControl AF: 0.0434

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 21, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Lissencephaly 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
Cadd	Benign	0.41
Dann	Benign	0.73
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs17283846; hg19: chr16-15790607;