SASH1

protein-coding

SAM and SH3 domain containing 1, the group of SAM and SH3 domain containing|Sterile alpha motif domain containing

Gene summary

This gene encodes a scaffold protein involved in the TLR4 signaling pathway that may stimulate cytokine production and endothelial cell migration in response to invading pathogens. The encoded protein has also been described as a potential tumor suppressor that may negatively regulate proliferation, apoptosis, and invasion of cancer cells, and reduced expression of this gene has been observed in multiple human cancers. Mutations in this gene may be associated with abnormal skin pigmentation in human patients. [provided by RefSeq, Oct 2016]

MANE transcript

NM_015278.5

Inheritance

AD, AR

ClinVar variants

P:15U:238B:63

Top phenotype

Cancer, alopecia, pigment dyscrasia, onychodystrophy, and keratoderma

gnomAD constraint

pLI —, LoF o/e 0.29

Max pathogenic AF

—

Genomic locus

chr6:148,272,304-148,552,044

External References & Databases

Ensembl (ENSG00000111961)

Transcript & Mutation Effects

hg38 • Region Span ~279.7 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

familial generalized lentiginosisSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007891

Submitter: Orphanet

pigmentation defects-palmoplantar keratoderma-skin carcinoma syndromeLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0018657

Submitter: Labcorp Genetics (formerly Invitae)

pigmentation defects-palmoplantar keratoderma-skin carcinoma syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0018657

Submitter: Orphanet

dyschromatosis universalis hereditaria 1STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0024524

Submitter: PanelApp Australia

dyschromatosis universalis hereditaria 1STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0024524

Submitter: Ambry Genetics

pigmentation defects-palmoplantar keratoderma-skin carcinoma syndromeLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0018657

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Cancer, alopecia, pigment dyscrasia, onychodystrophy, and keratodermaAR

Manifestation: Dental; Dermatologic; Oncologic

Intervention: Oncologic

Rationale: The condition can involve the development of squamous cell carcinomas, and awareness may allow surveilance in order to allow prompt diagnosis and management

Refs: 25315659; 26203640; 27659786; 27840890; 28407215; 29956681

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SASH1 variants in ClinVar

14 Conditions Cataloged

Inborn genetic diseasesTotal: 207

not specifiedTotal: 58

not providedTotal: 53

SASH1-related disorderTotal: 33

Dyschromatosis universalis hereditaria 1Total: 23

Cancer, alopecia, pigment dyscrasia, onychodystrophy, and keratodermaTotal: 8

Wilson diseaseTotal: 3

Palmoplantar keratodermaTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_015278.5. 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			3 clinvar	39 clinvar		42
missense		14 clinvar	226 clinvar	21 clinvar	3 clinvar	264
nonsense						0
start loss						0
frameshift	1 clinvar		1 clinvar			2
splice donor/acceptor (+/-2bp)			8 clinvar			8
Total	1	14	238	60	3	316

Highest pathogenic variant AF is 0.000032838525

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 42 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_015278.5	RefSeq	NP_056093.3	20	MANE Select
ENST00000367467.8	Ensembl	ENSP00000356437.3	20	MANE Select
NM_001346505.2	RefSeq	NP_001333434.1	20	Standard
NM_001346506.2	RefSeq	NP_001333435.1	17	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

protein polyubiquitination
positive regulation of endothelial cell migration
positive regulation of lipopolysaccharide-mediated signaling pathway
positive regulation of JUN kinase activity
positive regulation of angiogenesis

Molecular Function

protein C-terminus binding
protein kinase binding
mitogen-activated protein kinase kinase kinase binding
protein-containing complex scaffold activity

Cellular Component

protein-containing complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000367467
Coding exons: 20
Length: 279747
Individuals with no LoFs: 125700
Homozygous LoFs: 0
Heterozygous LoFs: 48
Defined: 125748
p: 0.000191

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.604	701	747	0.938	0.0000463	8082
Missense (PolyPhen)		252	314.69	0.80079		3414
Synonymous	-0.505	327	316	1.04	0.0000219	2512
Loss of Function	4.89	16	55.2	0.290	0.00000289	688

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00044	0.00043	rare
Latino/Admixed American	0.00032	0.00032	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.00034	0.00033	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.00016	0.00016	rare
South Asian	0.00014	0.00013	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: May have a role in a signaling pathway. Could act as a tumor suppressor.;

Recessive Scores

pRec: 0.112

Intolerance Scores

LoFtool: 0.521
RVIS EVS: -0.56
RVIS percentile EVS: 19.07

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.867

Gene Damage Prediction

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