16-15687197-A-G

Variant names:

• chr16-15687197-A-G
• rs8044738
• NM_017668.3:c.387-178A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_017668.3(NDE1):​c.387-178A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.66 in 1,516,290 control chromosomes in the GnomAD database, including 334,188 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.73 (40815 hom., cov: 31)
  • Exomes 𝑓: 0.65 (293373 hom.)
• Consequence: NDE1 NM_017668.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.379
• Publications: 10 publications found

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 Gene-Disease associations (from GenCC):

• lissencephaly 4

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: PanelApp Australia, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
• hydranencephaly

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• microlissencephaly

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• NDE1-related microhydranencephaly

  Inheritance: Unknown, AR Classification: SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 16-15687197-A-G is Benign according to our data. Variant chr16-15687197-A-G is described in ClinVar as Benign. ClinVar VariationId is 667642.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.887 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017668.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDE1	NM_017668.3	MANE Select	c.387-178A>G		intron	N/A	NP_060138.1
	NDE1	NM_001143979.2		c.387-178A>G		intron	N/A	NP_001137451.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDE1	ENST00000396354.6	TSL:1 MANE Select	c.387-178A>G		intron	N/A	ENSP00000379642.1
	NDE1	ENST00000396355.5	TSL:1	c.387-178A>G		intron	N/A	ENSP00000379643.1
	NDE1	ENST00000577101.6	TSL:4	c.387-178A>G		intron	N/A	ENSP00000461729.2

Frequencies

GnomAD3 genomes AF: 0.726 AC: 110147 AN: 151820 Hom.: 40753 Cov.: 31

Gnomad AFR AF: 0.894

Gnomad AMI AF: 0.729

Gnomad AMR AF: 0.706

Gnomad ASJ AF: 0.727

Gnomad EAS AF: 0.638

Gnomad SAS AF: 0.742

Gnomad FIN AF: 0.655

Gnomad MID AF: 0.725

Gnomad NFE AF: 0.644

Gnomad OTH AF: 0.713

GnomAD2 exomes AF: 0.691 AC: 96166 AN: 139152 AF XY: 0.694

Gnomad AFR exome AF: 0.908

Gnomad AMR exome AF: 0.702

Gnomad ASJ exome AF: 0.728

Gnomad EAS exome AF: 0.645

Gnomad FIN exome AF: 0.651

Gnomad NFE exome AF: 0.642

Gnomad OTH exome AF: 0.689

GnomAD4 exome AF: 0.653 AC: 890870 AN: 1364352 Hom.: 293373 Cov.: 28 AF XY: 0.655 AC XY: 441284 AN XY: 673390

African (AFR) AF: 0.902 AC: 28062 AN: 31124

American (AMR) AF: 0.705 AC: 24308 AN: 34462

Ashkenazi Jewish (ASJ) AF: 0.727 AC: 17625 AN: 24244

East Asian (EAS) AF: 0.606 AC: 21074 AN: 34796

South Asian (SAS) AF: 0.747 AC: 58514 AN: 78310

European-Finnish (FIN) AF: 0.647 AC: 21655 AN: 33454

Middle Eastern (MID) AF: 0.769 AC: 4290 AN: 5578

European-Non Finnish (NFE) AF: 0.635 AC: 676740 AN: 1065592

Other (OTH) AF: 0.680 AC: 38602 AN: 56792

GnomAD4 genome AF: 0.726 AC: 110270 AN: 151938 Hom.: 40815 Cov.: 31 AF XY: 0.726 AC XY: 53909 AN XY: 74250

African (AFR) AF: 0.894 AC: 37084 AN: 41472

American (AMR) AF: 0.706 AC: 10748 AN: 15224

Ashkenazi Jewish (ASJ) AF: 0.727 AC: 2521 AN: 3468

East Asian (EAS) AF: 0.639 AC: 3291 AN: 5152

South Asian (SAS) AF: 0.743 AC: 3572 AN: 4808

European-Finnish (FIN) AF: 0.655 AC: 6915 AN: 10564

Middle Eastern (MID) AF: 0.731 AC: 215 AN: 294

European-Non Finnish (NFE) AF: 0.644 AC: 43761 AN: 67942

Other (OTH) AF: 0.713 AC: 1501 AN: 2106

Alfa AF: 0.699 Hom.: 8585

Bravo AF: 0.735

Asia WGS AF: 0.697 AC: 2425 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jun 19, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.88
DANN	Benign	0.34
PhyloP100		-0.38
PromoterAI		-0.037	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs8044738; hg19: chr16-15781054; COSMIC: COSV61269821; COSMIC: COSV61269821;