chr16-15643570-CT-C

Variant names:

• chr16-15643570-CT-C
• rs796579453
• ENST00000396355.5:c.-512delT

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BS1

The ENST00000396355.5(NDE1):​c.-512delT variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0678 in 244,214 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 31)
  • Exomes 𝑓: 0.17 (0 hom.)
• Consequence: NDE1 ENST00000396355.5 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.176
• Publications: 0 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]

MIR484 (HGNC:32341): (microRNA 484) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Variant has high frequency in the NFE (0.169) population. However there is too low homozygotes in high coverage region: (expected more than 280, got 0).
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00147 (215/146220) while in subpopulation EAS AF = 0.00635 (32/5042). AF 95% confidence interval is 0.00462. There are 0 homozygotes in GnomAd4. There are 119 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NDE1	NM_001143979.2	c.-512delT		5_prime_UTR_variant	Exon 1 of 10		NP_001137451.1
NDE1	XM_006720897.5	c.-294delT		5_prime_UTR_variant	Exon 1 of 8		XP_006720960.1
NDE1	XM_047434258.1	c.-294delT		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.-512delT		5_prime_UTR_variant	Exon 1 of 10	1		ENSP00000379643.1
NDE1	ENST00000674888.1	n.-400delT		upstream_gene_variant				ENSP00000501936.1
MIR484	ENST00000606601.3	n.*199delT		downstream_gene_variant		6

Frequencies

GnomAD3 genomes AF: 0.00145 AC: 212 AN: 146170 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00237

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000616

Gnomad ASJ AF: 0.000296

Gnomad EAS AF: 0.00613

Gnomad SAS AF: 0.000215

Gnomad FIN AF: 0.00399

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000514

Gnomad OTH AF: 0.00251

GnomAD4 exome AF: 0.167 AC: 16348 AN: 97994 Hom.: 0 Cov.: 0 AF XY: 0.165 AC XY: 9373 AN XY: 56750

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.144 AC: 93 AN: 646

American (AMR) AF: 0.127 AC: 194 AN: 1532

Ashkenazi Jewish (ASJ) AF: 0.149 AC: 449 AN: 3016

East Asian (EAS) AF: 0.157 AC: 114 AN: 728

South Asian (SAS) AF: 0.166 AC: 3463 AN: 20830

European-Finnish (FIN) AF: 0.151 AC: 1040 AN: 6886

Middle Eastern (MID) AF: 0.0949 AC: 67 AN: 706

European-Non Finnish (NFE) AF: 0.172 AC: 10125 AN: 59032

Other (OTH) AF: 0.174 AC: 803 AN: 4618

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00147 AC: 215 AN: 146220 Hom.: 0 Cov.: 31 AF XY: 0.00167 AC XY: 119 AN XY: 71068

African (AFR) AF: 0.00242 AC: 97 AN: 40154

American (AMR) AF: 0.000615 AC: 9 AN: 14632

Ashkenazi Jewish (ASJ) AF: 0.000296 AC: 1 AN: 3380

East Asian (EAS) AF: 0.00635 AC: 32 AN: 5042

South Asian (SAS) AF: 0.000216 AC: 1 AN: 4640

European-Finnish (FIN) AF: 0.00399 AC: 36 AN: 9032

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 280

European-Non Finnish (NFE) AF: 0.000514 AC: 34 AN: 66150

Other (OTH) AF: 0.00249 AC: 5 AN: 2012

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.18
Mutation Taster		=299/1	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: rs796579453; hg19: chr16-15737427; COSMIC: COSV60022208; COSMIC: COSV60022208;