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 NM_001143979.2(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 NM_001143979.2 5_prime_UTR
• 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: 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: 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 VariationId 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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001143979.2. 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_001143979.2		c.-353A>G		5_prime_UTR	Exon 1 of 10	NP_001137451.1	Q9NXR1-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDE1	ENST00000396355.5	TSL:1	c.-353A>G		5_prime_UTR	Exon 1 of 10	ENSP00000379643.1	Q9NXR1-2
	NDE1	ENST00000911227.1		c.-231A>G		5_prime_UTR	Exon 1 of 9	ENSP00000581286.1
	NDE1	ENST00000963926.1		c.-329A>G		5_prime_UTR	Exon 1 of 10	ENSP00000633985.1

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

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Lissencephaly 4 (1)

Computational scores

Source: dbNSFP v4.9

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;