rs138559781

Variant names:

• chr16-15643740-A-G
• rs138559781
• ENST00000396355.5:c.-353A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The ENST00000674888.1(NDE1):​n.-231A>G variant causes a non coding transcript exon 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 ENST00000674888.1 non_coding_transcript_exon
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.145
• Publications: 2 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 -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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 9 AR,Unknown gene

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NDE1	ENST00000396355.5	c.-353A>G		5_prime_UTR_variant	Exon 1 of 10	1		ENSP00000379643.1
NDE1	ENST00000674888.1	n.-231A>G		non_coding_transcript_exon_variant	Exon 1 of 10			ENSP00000501936.1
NDE1	ENST00000674888.1	n.-231A>G		5_prime_UTR_variant	Exon 1 of 10			ENSP00000501936.1

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

African (AFR) AF: 0.00649 AC: 2 AN: 308

American (AMR) AF: 0.00617 AC: 2 AN: 324

Ashkenazi Jewish (ASJ) AF: 0.0157 AC: 21 AN: 1340

East Asian (EAS) AF: 0.00 AC: 0 AN: 220

South Asian (SAS) AF: 0.0172 AC: 243 AN: 14100

European-Finnish (FIN) AF: 0.00251 AC: 10 AN: 3984

Middle Eastern (MID) AF: 0.0221 AC: 5 AN: 226

European-Non Finnish (NFE) AF: 0.00741 AC: 287 AN: 38720

Other (OTH) AF: 0.00492 AC: 17 AN: 3452

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

African (AFR) AF: 0.00135 AC: 56 AN: 41564

American (AMR) AF: 0.00942 AC: 144 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0199 AC: 69 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.0160 AC: 77 AN: 4826

European-Finnish (FIN) AF: 0.00123 AC: 13 AN: 10600

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.00812 AC: 552 AN: 68012

Other (OTH) AF: 0.0114 AC: 24 AN: 2108

Alfa AF: 0.00531 Hom.: 5

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

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		0.14
PromoterAI		0.058	Neutral
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

Other links and lift over

dbSNP: rs138559781; hg19: chr16-15737597;