GeneBe

SRCAP

protein-coding

Snf2 related CREBBP activator protein, the group of Small nucleolar RNA protein coding host genes|SRCAP complex

Gene summary

This gene encodes the core catalytic component of the multiprotein chromatin-remodeling SRCAP complex. The encoded protein is an ATPase that is necessary for the incorporation of the histone variant H2A.Z into nucleosomes. It can function as a transcriptional activator in Notch-mediated, CREB-mediated and steroid receptor-mediated transcription. Mutations in this gene cause Floating-Harbor syndrome, a rare disorder characterized by short stature, language deficits and dysmorphic facial features. [provided by RefSeq, Feb 2012]

MANE transcript

NM_006662.3

Inheritance

AD

ClinVar variants

P:127U:1364B:777

Top phenotype

Floating-Harbor syndrome; Developmental delay, hypotonia, musculoskeletal defects, and behavioral abnormalities

gnomAD constraint

pLI —, LoF o/e 0.05

Max pathogenic AF

—

Genomic locus

chr16:30,698,209-30,741,409

External References & Databases

Ensembl (ENSG00000080603)NCBI Gene (10847)OMIM (611421)HGNC:16974GenCCUniProt (Q6ZRS2)AlphaFoldClinVar (SRCAP)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~43.2 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

developmental delay, hypotonia, musculoskeletal defects, and behavioral abnormalitiesSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0859202

Submitter: Labcorp Genetics (formerly Invitae)

developmental delay, hypotonia, musculoskeletal defects, and behavioral abnormalitiesSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0859202

Submitter: PanelApp Australia

Floating-Harbor syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007621

Submitter: Ambry Genetics

Floating-Harbor syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007621

Submitter: Orphanet

developmental delay, hypotonia, musculoskeletal defects, and behavioral abnormalitiesSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0859202

Submitter: G2P

Floating-Harbor syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007621

Submitter: Labcorp Genetics (formerly Invitae)

Floating-Harbor syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007621

Submitter: ClinGen

*SRCAP* was first reported in relation to autosomal dominant Floating Harbor Syndrome (FHS) in 2012 (Hood et al., PMID: 22265015). A rare genetic disorder, FHS is characterized by short stature, delayed bone age, delayed speech development, and distinctive facial features – the face is triangular with deep-set eyes, long eyelashes, bulbous nose, wide columella, short philtrum, and thin lips. Additional phenotypes including mild to moderate intellectual disability have also been reported. The specific phenotypes and severity of FHS vary greatly from one person to another and also by age. Fourteen variants (frameshift (9) and nonsense (5)) mostly de novo (9), reported in 14 probands in 5 publications are included in this curation (PMIDs: 22265015, 22965468, 25433523, 23621943, 30425916). Two of the variants, c.7330C>T (p.Arg2444*) and c.7303C>T (p.Arg2435*) on exon 34, are recurrent and have been reported in sixteen and ten unrelated individuals, respectively (PMID: 22265015, 22965468, 25433523, 30425916, 23621943). The mechanism of pathogenicity is reported as haploinsufficiency. While more evidence is available in the literature, the maximum score for genetic evidence (12 points) has been reached. In summary, there is definitive evidence to support the relationship between *SRCAP* and Floating Harbor Syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism expert panel on August 1, 2023 (SOP Version 9).

Floating-Harbor syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007621

Submitter: G2P

developmental delay, hypotonia, musculoskeletal defects, and behavioral abnormalitiesDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0859202

Submitter: Ambry Genetics

Floating-Harbor syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007621

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Floating-Harbor syndrome; Developmental delay, hypotonia, musculoskeletal defects, and behavioral abnormalitiesAD

Manifestation: Craniofacial; Genitourinary; Musculoskeletal; Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 7588969; 16523514; 20358590; 22265015; 23763483; 33909990Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SRCAP variants in ClinVar

25 Conditions Cataloged
not providedTotal: 1888
Floating-Harbor syndromeTotal: 522
Developmental delay, hypotonia, musculoskeletal defects, and behavioral abnormalitiesTotal: 487
Inborn genetic diseasesTotal: 446
not specifiedTotal: 311
SRCAP-related disorderTotal: 124
Neurodevelopmental disorderTotal: 31
Monogenic short statueTotal: 6

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_006662.3. 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.

EffectPLPVUSLBBSum
synonymous
16
clinvar
566
clinvar
5
clinvar
 587
missense
6
clinvar
1327
clinvar
204
clinvar
2
clinvar
 1539
nonsense
16
clinvar
21
clinvar
7
clinvar
 44
start loss
0
frameshift
28
clinvar
46
clinvar
7
clinvar
 81
splice donor/acceptor (+/-2bp)
2
clinvar
8
clinvar
7
clinvar
 17
Total4681136477072268

Highest pathogenic variant AF is 0.00018591479

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 16 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_006662.3RefSeqNP_006653.232MANE Select
ENST00000262518.9EnsemblENSP00000262518.432MANE Select
ENST00000411466.7EnsemblENSP00000405186.332Standard
ENST00000483083.3EnsemblENSP00000483329.118Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Pathways Affected in Adenoid Cystic Carcinoma

Biological Process

  • chromatin remodeling
  • regulation of transcription by RNA polymerase II
  • viral process
  • gene silencing
  • histone acetylation

Molecular Function

  • DNA binding
  • transcription coactivator activity
  • helicase activity
  • histone acetyltransferase activity
  • protein binding

Cellular Component

  • Swr1 complex
  • nucleus
  • nucleoplasm
  • Golgi apparatus
  • nuclear body

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000262518
Coding exons
32
Length
46073
Individuals with no LoFs
125732
Homozygous LoFs
0
Heterozygous LoFs
16
Defined
125748
p
0.0000636
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense2.1316341.89e+30.8620.00011820343
Missense (PolyPhen)147225.750.651172176
Synonymous-3.118507421.150.00004197482
Loss of Function9.8161240.04850.000007541310

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000180.00018rare
Latino/Admixed American00.0absent
Ashkenazi Jewish0.000200.00020rare
East Asian00.0absent
Finnish0.0000460.000046rare
European (Non-Finnish)0.0000710.000062rare
South Asian0.0000980.000098rare
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Catalytic component of the SRCAP complex which mediates the ATP-dependent exchange of histone H2AZ/H2B dimers for nucleosomal H2A/H2B, leading to transcriptional regulation of selected genes by chromatin remodeling. Acts as a coactivator for CREB-mediated transcription, steroid receptor-mediated transcription, and Notch-mediated transcription. {ECO:0000269|PubMed:10347196, ECO:0000269|PubMed:11522779, ECO:0000269|PubMed:14500758, ECO:0000269|PubMed:16024792, ECO:0000269|PubMed:16634648, ECO:0000269|PubMed:17617668}.;
Disease
DISEASE: Floating-Harbor syndrome (FLHS) [MIM:136140]: A rare genetic disorder characterized by proportionate short stature, delayed bone age, delayed speech development, and typical facial features. The face is triangular with deep-set eyes, long eyelashes, bulbous nose, wide columella, short philtrum, and thin lips. {ECO:0000269|PubMed:22265015}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.0771

Intolerance Scores

LoFtool
0.00579
RVIS EVS
-4.14
RVIS percentile EVS
0.15

Essentials

Essential (CRISPR)
E
Essential (CRISPR2)
E
Essential (gene trap)
E
Indispensability pred.
E
Indispensability score
0.847

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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