16-15643740-A-G

Position:

• chr16-15643740-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The ENST00000396355.5(NDE1):​c.-353A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00711 in 214,940 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0062 (9 hom., cov: 32)
  • Exomes 𝑓: 0.0094 (9 hom.)
• Consequence: NDE1 ENST00000396355.5 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.145

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 16-15643740-A-G is Benign according to our data. Variant chr16-15643740-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 318029.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00619 (942/152266) while in subpopulation SAS AF= 0.016 (77/4826). AF 95% confidence interval is 0.0131. There are 9 homozygotes in gnomad4. There are 485 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NDE1	NM_001143979.2	c.-353A>G		5_prime_UTR_variant	1/10		NP_001137451.1
NDE1	XM_006720897.5	c.-135A>G		5_prime_UTR_variant	1/8		XP_006720960.1
NDE1	XM_047434258.1	c.-135A>G		5_prime_UTR_variant	1/8		XP_047290214.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NDE1	ENST00000396355.5	c.-353A>G		5_prime_UTR_variant	1/10	1		ENSP00000379643	P1
NDE1	ENST00000674888.1	c.-231A>G		5_prime_UTR_variant, NMD_transcript_variant	1/10			ENSP00000501936

Frequencies

GnomAD3 genomes AF: 0.00621 AC: 945 AN: 152148 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.00140

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00943

Gnomad ASJ AF: 0.0199

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0164

Gnomad FIN AF: 0.00123

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.00809

Gnomad OTH AF: 0.0115

GnomAD4 exome AF: 0.00937 AC: 587 AN: 62674 Hom.: 9 Cov.: 0 AF XY: 0.0109 AC XY: 371 AN XY: 34150

Gnomad4 AFR exome AF: 0.00649

Gnomad4 AMR exome AF: 0.00617

Gnomad4 ASJ exome AF: 0.0157

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0172

Gnomad4 FIN exome AF: 0.00251

Gnomad4 NFE exome AF: 0.00741

Gnomad4 OTH exome AF: 0.00492

GnomAD4 genome AF: 0.00619 AC: 942 AN: 152266 Hom.: 9 Cov.: 32 AF XY: 0.00651 AC XY: 485 AN XY: 74444

Gnomad4 AFR AF: 0.00135

Gnomad4 AMR AF: 0.00942

Gnomad4 ASJ AF: 0.0199

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0160

Gnomad4 FIN AF: 0.00123

Gnomad4 NFE AF: 0.00812

Gnomad4 OTH AF: 0.0114

Alfa AF: 0.00688 Hom.: 2

Bravo AF: 0.00639

Asia WGS AF: 0.00693 AC: 24 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Lissencephaly 4 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	5.8
DANN	Benign	0.59

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: rs138559781; hg19: chr16-15737597;