LIN28A

protein-coding

lin-28 homolog A, the group of Zinc fingers CCHC-type

Gene summary

This gene encodes a LIN-28 family RNA-binding protein that acts as a posttranscriptional regulator of genes involved in developmental timing and self-renewal in embryonic stem cells. The encoded protein functions through direct interaction with target mRNAs and by disrupting the maturation of certain miRNAs involved in embryonic development. This protein prevents the terminal processing of the LET7 family of microRNAs which are major regulators of cellular growth and differentiation. Aberrant expression of this gene is associated with cancer progression in multiple tissues. [provided by RefSeq, Sep 2015]

Previous symbols:

LIN28

MANE transcript

NM_024674.6

Inheritance

—

ClinVar variants

U:24B:1

Top phenotype

—

gnomAD constraint

pLI —, LoF o/e 0.45

Max pathogenic AF

—

Genomic locus

chr1:26,410,817-26,429,728

External References & Databases

Ensembl (ENSG00000131914)

Transcript & Mutation Effects

hg38 • Region Span ~18.9 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

No GenCC data available for this gene.

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to LIN28A variants in ClinVar

2 Conditions Cataloged

not specifiedTotal: 22

not providedTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_024674.6. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous					1 clinvar	1
missense			22 clinvar			22
nonsense			1 clinvar			1
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			1 clinvar			1
Total	0	0	24	0	1	25

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 6 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_024674.6	RefSeq	NP_078950.1	4	MANE Select
ENST00000326279.11	Ensembl	ENSP00000363314.3	4	MANE Select
ENST00000254231.4	Ensembl	ENSP00000254231.4	4	Standard
ENST00001060610.1	Ensembl	ENSP00000730426.1	3	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
lin28a	Danio rerio	Structure: post-vent region Quality: decreased length abnormal

Gene / Model

Organism

Observed Phenotype

lin28a

Danio rerio

Structure: post-vent region

Quality: decreased length

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Cardiac Progenitor Differentiation
Developmental Biology
Transcriptional regulation of pluripotent stem cells

Biological Process

regulation of transcription, DNA-templated
germ cell development
miRNA catabolic process
negative regulation of translation
stem cell population maintenance

Molecular Function

G-quadruplex RNA binding
DNA binding
RNA binding
protein binding
zinc ion binding

Cellular Component

P-body
nucleus
nucleolus
cytoplasm
rough endoplasmic reticulum

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000326279
Coding exons: 4
Length: 18945
Individuals with no LoFs: 125740
Homozygous LoFs: 0
Heterozygous LoFs: 7
Defined: 125747
p: 0.0000278

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.714	104	127	0.821	0.00000650	1367
Missense (PolyPhen)		19	31.436	0.60441		376
Synonymous	0.148	49	50.3	0.973	0.00000251	401
Loss of Function	1.52	4	8.90	0.449	4.42e-7	106

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000087	0.000087	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000027	0.000026	rare
South Asian	0.000033	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: RNA-binding protein that inhibits processing of pre-let- 7 miRNAs and regulates translation of mRNAs that control developmental timing, pluripotency and metabolism (PubMed:21247876). Seems to recognize a common structural G- quartet (G4) feature in its miRNA and mRNA targets (Probable). 'Translational enhancer' that drives specific mRNAs to polysomes and increases the efficiency of protein synthesis. Its association with the translational machinery and target mRNAs results in an increased number of initiation events per molecule of mRNA and, indirectly, in mRNA stabilization. Binds IGF2 mRNA, MYOD1 mRNA, ARBP/36B4 ribosomal protein mRNA and its own mRNA. Essential for skeletal muscle differentiation program through the translational up-regulation of IGF2 expression. Suppressor of microRNA (miRNA) biogenesis, including that of let-7, miR107, miR-143 and miR-200c. Specifically binds the miRNA precursors (pre-miRNAs), recognizing an 5'-GGAG-3' motif found in pre-miRNA terminal loop, and recruits TUT4 AND tut7 uridylyltransferaseS. This results in the terminal uridylation of target pre-miRNAs. Uridylated pre-miRNAs fail to be processed by Dicer and undergo degradation. The repression of let- 7 expression is required for normal development and contributes to maintain the pluripotent state by preventing let-7-mediated differentiation of embryonic stem cells (PubMed:18951094, PubMed:19703396, PubMed:22118463, PubMed:22898984). Localized to the periendoplasmic reticulum area, binds to a large number of spliced mRNAs and inhibits the translation of mRNAs destined for the ER, reducing the synthesis of transmembrane proteins, ER or Golgi lumen proteins, and secretory proteins. Binds to and enhances the translation of mRNAs for several metabolic enzymes, such as PFKP, PDHA1 or SDHA, increasing glycolysis and oxidative phosphorylation. Which, with the let-7 repression may enhance tissue repair in adult tissue (By similarity). {ECO:0000250|UniProtKB:Q8K3Y3, ECO:0000269|PubMed:18951094, ECO:0000269|PubMed:19703396, ECO:0000269|PubMed:21247876, ECO:0000269|PubMed:22118463, ECO:0000269|PubMed:22898984, ECO:0000305}.;

Recessive Scores

pRec: 0.133

Intolerance Scores

RVIS EVS: -0.3
RVIS percentile EVS: 32.62

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.283

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium