16-15667576-C-T

Variant names:

• chr16-15667576-C-T
• rs4781679
• NM_017668.3:c.237+137C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_017668.3(NDE1):​c.237+137C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000116 in 861,132 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 27)
  • Exomes 𝑓: 0.0000012 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NDE1 NM_017668.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.227
• Publications: 11 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: Labcorp Genetics (formerly Invitae), G2P, Laboratory for Molecular Medicine, Ambry Genetics
• microcephaly with lissencephaly and/or hydranencephaly

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDE1	NM_017668.3	MANE Select	c.237+137C>T		intron	N/A	NP_060138.1	Q9NXR1-2
	NDE1	NM_001143979.2		c.237+137C>T		intron	N/A	NP_001137451.1	Q9NXR1-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDE1	ENST00000396354.6	TSL:1 MANE Select	c.237+137C>T		intron	N/A	ENSP00000379642.1	Q9NXR1-2
	NDE1	ENST00000396355.5	TSL:1	c.237+137C>T		intron	N/A	ENSP00000379643.1	Q9NXR1-2
	NDE1	ENST00000577101.6	TSL:4	c.237+137C>T		intron	N/A	ENSP00000461729.2	I3L522

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 150246 Hom.: 0 Cov.: 27

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000116 AC: 1 AN: 861132 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 444734

African (AFR) AF: 0.00 AC: 0 AN: 21134

American (AMR) AF: 0.00 AC: 0 AN: 34872

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21746

East Asian (EAS) AF: 0.00 AC: 0 AN: 33346

South Asian (SAS) AF: 0.00 AC: 0 AN: 69170

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37336

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3042

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 599724

Other (OTH) AF: 0.0000245 AC: 1 AN: 40762

GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 150362 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 73218

African (AFR) AF: 0.00 AC: 0 AN: 40840

American (AMR) AF: 0.00 AC: 0 AN: 14980

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5094

South Asian (SAS) AF: 0.00 AC: 0 AN: 4800

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10062

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67830

Other (OTH) AF: 0.00 AC: 0 AN: 2092

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.95
DANN	Benign	0.92
PhyloP100		0.23

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: rs4781679; hg19: chr16-15761433;