16-15643320-G-A

Variant names:

• chr16-15643320-G-A
• rs376603273
• ENST00000396355.5:c.-773G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Moderate BP6_Very_Strong BS2

The ENST00000000000(MIR484):​n.20G>A variant causes a splice region, non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00206 in 473,166 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0024 (4 hom.)
• Consequence: MIR484 ENST00000000000 splice_region, non_coding_transcript_exon
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.09
• Publications: 1 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]

MARF1 (HGNC:29562): (meiosis regulator and mRNA stability factor 1) This gene encodes a putative peroxisomal protein that appears to be conserved across Euteleostomi. In humans, it may be autoantigenic. [provided by RefSeq, Jul 2010]

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).
• BP6: Variant 16-15643320-G-A is Benign according to our data. Variant chr16-15643320-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 318016.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 4 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MARF1	NM_014647.4	c.-361C>T		upstream_gene_variant		ENST00000396368.8	NP_055462.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MARF1	ENST00000396368.8	c.-361C>T		upstream_gene_variant		1	NM_014647.4	ENSP00000379654.3

Frequencies

GnomAD3 genomes AF: 0.00126 AC: 192 AN: 152076 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000786

Gnomad ASJ AF: 0.0107

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00311

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00163

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00202 AC: 327 AN: 162188 AF XY: 0.00232

Gnomad AFR exome AF: 0.000388

Gnomad AMR exome AF: 0.000528

Gnomad ASJ exome AF: 0.00738

Gnomad EAS exome AF: 0.0000941

Gnomad FIN exome AF: 0.0000594

Gnomad NFE exome AF: 0.00192

Gnomad OTH exome AF: 0.00231

GnomAD4 exome AF: 0.00244 AC: 783 AN: 320972 Hom.: 4 Cov.: 0 AF XY: 0.00277 AC XY: 508 AN XY: 183274

African (AFR) AF: 0.000141 AC: 1 AN: 7112

American (AMR) AF: 0.000575 AC: 16 AN: 27844

Ashkenazi Jewish (ASJ) AF: 0.00854 AC: 91 AN: 10652

East Asian (EAS) AF: 0.00 AC: 0 AN: 8326

South Asian (SAS) AF: 0.00532 AC: 318 AN: 59788

European-Finnish (FIN) AF: 0.0000695 AC: 2 AN: 28776

Middle Eastern (MID) AF: 0.00921 AC: 23 AN: 2496

European-Non Finnish (NFE) AF: 0.00178 AC: 288 AN: 161780

Other (OTH) AF: 0.00310 AC: 44 AN: 14198

GnomAD4 genome AF: 0.00126 AC: 192 AN: 152194 Hom.: 0 Cov.: 32 AF XY: 0.00124 AC XY: 92 AN XY: 74408

African (AFR) AF: 0.000217 AC: 9 AN: 41536

American (AMR) AF: 0.000785 AC: 12 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0107 AC: 37 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00311 AC: 15 AN: 4826

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10594

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00163 AC: 111 AN: 67980

Other (OTH) AF: 0.00189 AC: 4 AN: 2112

Alfa AF: 0.00243 Hom.: 1

Bravo AF: 0.00124

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

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. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	20
DANN	Benign	0.94
PhyloP100		1.1
PromoterAI		-0.12	Neutral
Mutation Taster		=296/4	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: rs376603273; hg19: chr16-15737177; COSMIC: COSV107422948; COSMIC: COSV107422948;