SLFN14

protein-coding

schlafen family member 14, the group of Schlafen family

Gene summary

The protein encoded by this gene plays an important role in platelet formation and function. Defects in this gene are a cause of thrombocytopenia with excessive bleeding. [provided by RefSeq, Jul 2016]

MANE transcript

NM_001129820.2

Inheritance

AD, AR

ClinVar variants

P:5U:164B:48

Top phenotype

Bleeding disorder, platelet-type, 20

gnomAD constraint

pLI —, LoF o/e 0.62

Max pathogenic AF

—

Genomic locus

chr17:35,543,985-35,560,819

External References & Databases

Ensembl (ENSG00000236320)

Transcript & Mutation Effects

hg38 • Region Span ~16.8 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

platelet-type bleeding disorder 20MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0014830

Submitter: Ambry Genetics

platelet-type bleeding disorder 20STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014830

Submitter: Labcorp Genetics (formerly Invitae)

platelet-type bleeding disorder 20STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014830

Submitter: PanelApp Australia

platelet-type bleeding disorder 20SUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0014830

Submitter: Orphanet

platelet-type bleeding disorder 20MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0014830

Submitter: ClinGen

*SLFN14* was first reported in relation to autosomal dominant platelet-type bleeding disorder 20 in 2015 (Fletcher et al, PMID: 26280575). The SLFN14 gene encodes an RNA endoribonuclease protein that regulates ribosomal RNA degradation. Platelet-type bleeding disorder 20 is characterized by moderate thrombocytopenia, enlarged platelets, reduce ATP secretion and aggregation in response to ADP, collagen, and protease activated receptor-1 (PAR-1) and a bleeding diathesis. Evidence supporting this gene-disease curation includes case level data and experimental data. Summary of Case Level Data (4.25 points): Six unique missense variants have been reported in humans. Variants in this gene have been reported in at least 9 probands in 6 publications (Fletcher et al., 2015, PMID: 26280575; Marconi et al., 2016, PMID: 26769223; Saes et al., 2019, PMID: 30431218; Turro et al., 2020, PMID: 32581362; Ang et al., 2022, PMID: 36237120; Polokhov et al., 2023, PMID: 37041648). Variants in this gene segregated with disease in at least 12 additional family members. Summary of Experimental Evidence (4 points): The gene-disease relationship is supported by expression studies (Fletcher et al., 2015, PMID: 26280575), biochemical function (Pisareva et al., 2015, PMID: 25996083), functional alteration (patient and non-patient cells) (Ver Donck et al., 2023, PMID: 36790527; Fletcher et al., 2018, PMID: 29678925; Marconi et al., 2016, PMID: 26769223), and a mouse model system (Stapley et al., 2021, PMID: 33496736). In summary, there is moderate evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This gene-disease relationship was originally curated by the ClinGen Hemostasis and Thrombosis (H/T) Gene Curation Expert Panel using the Gene Clinical Validity Standard Operating Procedures (SOP), Version 7 and approved on May 25, 2022. This gene-disease pair was re-curated on November 4th, 2024 using Gene Clinical Validity Standard Operating Procedures (SOP), Version 11.

Clinical Genomic Database (CGD)

Bleeding disorder, platelet-type, 20AR

Manifestation: Hematologic

Intervention: Hematologic

Rationale: Individuals have increased bleeding tendency, and awareness may allow preventive measures and early management of bleeding complications

Refs: 26280575; 26769223

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SLFN14 variants in ClinVar

8 Conditions Cataloged

Inborn genetic diseasesTotal: 127

not providedTotal: 52

not specifiedTotal: 36

Platelet-type bleeding disorder 20Total: 30

SLFN14-related disorderTotal: 27

ThrombocytopeniaTotal: 7

Abnormal bleedingTotal: 7

Bleeding and platelet disordersTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001129820.2. 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	21 clinvar	2 clinvar	24
missense	1 clinvar	3 clinvar	145 clinvar	25 clinvar		174
nonsense			10 clinvar			10
start loss						0
frameshift	1 clinvar		7 clinvar			8
splice donor/acceptor (+/-2bp)			1 clinvar			1
Total	2	3	164	46	2	217

Highest pathogenic variant AF is 0.000005156274

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 7 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001129820.2	RefSeq	NP_001123292.1	4	MANE Select
ENST00000674182.1	Ensembl	ENSP00000501524.1	4	MANE Select
ENST00000415846.3	Ensembl	ENSP00000391101.2	4	Standard
ENST00000415846.4	Ensembl	ENSP00000391101.2	4	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

mRNA catabolic process
rRNA catabolic process
platelet maturation
cellular response to magnesium ion
cellular response to manganese ion

Molecular Function

endoribonuclease activity
ATP binding
ribosome binding

Cellular Component

nucleus
cytoplasm

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000415846
Coding exons: 4
Length: 9974
Individuals with no LoFs: 0
Homozygous LoFs: 0
Heterozygous LoFs: 0
Defined: 0
p: 0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.43	318	465	0.684	0.0000225	6013
Missense (PolyPhen)		89	137.81	0.64581		1859
Synonymous	2.20	134	170	0.786	0.00000838	1732
Loss of Function	1.90	18	29.1	0.619	0.00000152	403

Population LoF Frequency

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

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Protein SLFN14: Shows no ribosome-associated and endoribonuclease activities. {ECO:0000269|PubMed:25996083}.;

Intolerance Scores

RVIS EVS: 2.71
RVIS percentile EVS: 98.93

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.310

Gene Damage Prediction

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